ABCMdb

ABCC7 p.Phe508Ala

ClinVar:	c.1523T>C , p.Phe508Ser ? , not provided c.1523T>G , p.Phe508Cys N , Benign
CF databases:	c.1521_1523delCTT , p.Phe508del D , CF-causing c.1523T>C , p.Phe508Ser (CFTR1) D , This mutation was found in a patient with CBAVD. c.1523T>G , p.Phe508Cys (CFTR1) ? ,
Predicted by SNAP2:	A: D (95%), C: D (75%), D: D (95%), E: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Structure of the human multidrug resistance protei... J Mol Biol. 2006 Jun 16;359(4):940-9. Epub 2006 May 2. Ramaen O, Leulliot N, Sizun C, Ulryck N, Pamlard O, Lallemand JY, Tilbeurgh H, Jacquet E
Structure of the human multidrug resistance protein 1 nucleotide binding domain 1 bound to Mg2+/ATP reveals a non-productive catalytic site.
J Mol Biol. 2006 Jun 16;359(4):940-9. Epub 2006 May 2., 2006-06-16 [PMID:16697012]

Abstract [show]
Human multidrug resistance protein 1 (MRP1) is a membrane protein that belongs to the ATP-binding cassette (ABC) superfamily of transport proteins. MRP1 contributes to chemotherapy failure by exporting a wide range of anti-cancer drugs when over expressed in the plasma membrane of cells. Here, we report the first high-resolution crystal structure of human MRP1-NBD1. Drug efflux requires energy resulting from hydrolysis of ATP by nucleotide binding domains (NBDs). Contrary to the prokaryotic NBDs, the extremely low intrinsic ATPase activity of isolated MRP1-NBDs allowed us to obtain the structure of wild-type NBD1 in complex with Mg2+/ATP. The structure shows that MRP1-NBD1 adopts a canonical fold, but reveals an unexpected non-productive conformation of the catalytic site, providing an explanation for the low intrinsic ATPase activity of NBD1 and new hypotheses on the cooperativity of ATPase activity between NBD1 and NBD2 upon heterodimer formation.

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63 Structure based sequence alignment of MRP1-NBD1 with MRP1-NBD2, h-CFTR-NBD1 (pdb code 1xmi, F508A F429S H667R mutant), BtuCD (pdb code 1l7v), TAP1 (pdb code 1jj7), MJ0796 (pdb code 1l2t, E171Q mutant), MJ1267 (pdb code 1g9x, N31C mutant), HisP (pdb code 1b0u) and HlyB-NBD (pdb code 1mt0). Login to comment

[hide] Impact of the deltaF508 mutation in first nucleoti... J Biol Chem. 2005 Jan 14;280(2):1346-53. Epub 2004 Nov 3. Lewis HA, Zhao X, Wang C, Sauder JM, Rooney I, Noland BW, Lorimer D, Kearins MC, Conners K, Condon B, Maloney PC, Guggino WB, Hunt JF, Emtage S
Impact of the deltaF508 mutation in first nucleotide-binding domain of human cystic fibrosis transmembrane conductance regulator on domain folding and structure.
J Biol Chem. 2005 Jan 14;280(2):1346-53. Epub 2004 Nov 3., 2005-01-14 [PMID:15528182]

Abstract [show]
Cystic fibrosis is caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR), commonly the deletion of residue Phe-508 (DeltaF508) in the first nucleotide-binding domain (NBD1), which results in a severe reduction in the population of functional channels at the epithelial cell surface. Previous studies employing incomplete NBD1 domains have attributed this to aberrant folding of DeltaF508 NBD1. We report structural and biophysical studies on complete human NBD1 domains, which fail to demonstrate significant changes of in vitro stability or folding kinetics in the presence or absence of the DeltaF508 mutation. Crystal structures show minimal changes in protein conformation but substantial changes in local surface topography at the site of the mutation, which is located in the region of NBD1 believed to interact with the first membrane spanning domain of CFTR. These results raise the possibility that the primary effect of DeltaF508 is a disruption of proper interdomain interactions at this site in CFTR rather than interference with the folding of NBD1. Interestingly, increases in the stability of NBD1 constructs are observed upon introduction of second-site mutations that suppress the trafficking defect caused by the DeltaF508 mutation, suggesting that these suppressors might function indirectly by improving the folding efficiency of NBD1 in the context of the full-length protein. The human NBD1 structures also solidify the understanding of CFTR regulation by showing that its two protein segments that can be phosphorylated both adopt multiple conformations that modulate access to the ATPase active site and functional interdomain interfaces.

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40 Crystallization and Data Collection-Crystallization leads at 4 °C from hNBD1-2b-F508A at 6-17 mg/ml 4 °C were optimized using microseeding. Login to comment
46 Structure Determination and Refinement-Structures were determined by molecular replacement using mNBD1 (for hNBD1-2b-F508A) or hNBD1-2b-F508A (for hNBD1-7a-⌬F508) as the search model with the program MolRep (16) and manually rebuilt using the program XtalView (17) over several cycles of refinement with CNX (18) and/or Refmac (16). Login to comment
48 The refined model of hNBD1-2b-F508A includes residues 388-411 and 429-671 in molecule A; 389-413, 429-532, 539-541, and 547-671 in molecule B; 389-415 and 429-671 in molecule C; 388-410 and 426-672 in molecule D; 389-411 and 429-671 in molecule E; 1 ATP/ TABLE I Human NBD1 proteins Thermodynamic values are listed for those proteins analyzed in equilibrium denaturation experiments. Login to comment
76 Recombinant proteins harboring the F508A mutation gave higher yields than the equivalent proteins with phenylalanine at position 508, whereas constructs with the ⌬F508 mutation consistently gave lower yields. Login to comment
82 Crystal Structure of hNBD1 Shows That Regulatory Protein Segments Adopt Multiple Conformations Altering Access to the Active Site-High-resolution diffraction data were obtained for hNBD1-2b-F508A, containing two solubilizing mutations (F429S and H667R) in addition to the F508A substitution (Table II). Login to comment
85 With the exception of the RI and RE segments, the structure of hNBD1-2b-F508A closely matches that of mNBD1. Login to comment
86 Least squares superposition of the remainder of the F1-type core and ABCbeta subdomains yields a 0.46-Å root mean square deviation (rmsd) for 127 C-␣ atoms, only slightly exceeding the 0.39-Å rmsd observed after superposition of the different molecules within the asymmetric unit of the crystal structure of hNBD1- 2b-F508A. Login to comment
91 We concluded that these differences re- TABLE II Statistics of structure determination and refinement hNBD1-2b-F508A hNBD1-7a-⌬F508 Data collection Resolution range 2.25-27.3 Å 2.25-26.7 Å Space Group C2221 P43212 a 144.46 Å 59.79 Å b 154.02 Å 59.79 Å c 136.09 Å 144.40 Å Completeness (overall/outer shell) 99.9%/99.9% 99.8%/99.8% Rsym (overall/outer shell)a 8.5%/40.7% 8.3%/41.7% I/␴(I) (overall/outershell) 4.3/1.2 7.5/1.6 Refinement Resolution range 2.25-27.3 Å 2.30-25.0 Å Rfree (overall/outer shell)b 26.5%/31.0% 28.0%/32.1% R (overall/outer shell)c 21.2%/28.0% 22.0%/22.1% Waters 704 135 rmsd bond lengths 0.006 Å 0.010 Å rmsd angles 1.0° 1.3° Average B-factorsd 32.5 34.9 Core Ramachandran 92.9% 93.1% Allowed Ramachandran 6.7% 6.4% Disallowed Ramachandran 0.2% 0.0% a Rsym ϭ ⌺hkl⌺i͉Ii(hkl-)͗(I(hkl)͉͘/⌺hkl⌺iIi(hkl), where Ii is the intensity of the observation and ͗I͘ is the mean intensity of the reflection. Login to comment
98 Although the conformation of the regulatory segments observed in the crystal structure of hNBD1-2b-F508A would preclude formation of a canonical ATP-sandwich complex with NBD2 because of a steric overlap at the interface, their dramatic change in conformation compared with the crystal structure of mNBD1 confirms our prediction that these segments of NBD1 are conformationally dynamic. Login to comment
101 It shows only minor differences compared with hNBD1-2b-F508A except in the immediate vicinity of the deletion of Phe-508 (Fig. 2) and at the regulatory seg- FIG. 1. Login to comment
109 Regions with conformational differences are shown in cyan for hNBD1-2b-F508A (molecule E), blue for hNBD1-7a-⌬F508, and gold for mNBD1 (molecule B). Login to comment
113 Superposition of the F1-type core and ABCbeta subdomains with those in hNBD1-2b-F508A gives an rmsd of 0.51 Å for 127 C-␣ atoms, similar to the deviations observed between the different protomers in that structure. Login to comment
114 The ABC␣ subdomain is rotated by 6° relative to its position in hNBD1-2b-F508A but is largely conserved in structure, exhibiting an rmsd of 0.87Å for the superposition of 49 C-␣ atoms. Login to comment
116 However, the position of ␣-helix 9b in the RE is very similar in the structures of hNBD1-7a-⌬F508 and mNBD1 (and different from the position observed in the structure of hNBD1-2b-F508A), suggesting that this may represent a preferred conformation of the dynamically flexible RE. Login to comment
119 A, stereo image of conformation of Phe-508 loop region in mNBD1 (gold), hNBD1-2b-F508A (cyan), and hNBD1-7a-⌬F508 (blue). Login to comment
120 B and C, worm diagrams of hNBD1-2b-F508A (B) and hNBD1-7a-⌬F508 (C). Login to comment
125 D and E, surface properties of hNBD1-2b-F508A (D) and hNBD1-7a-⌬F508 (E) in same orientations as in B and C. Login to comment
126 Residues 507-510 in hNBD1-2b-F508A structure have been replaced with those from the mNBD1 structure to provide an image representative of the wild-type human protein. Login to comment
133 The superposition of the three available NBD1 crystal structures (mNBD1, hNBD1-2b-F508A, and hNBD1-7a-⌬F508) based on least squares alignment of ␣-helices 3 and 4 demonstrates that the conformation is extremely similar even in the immediate vicinity of the deletion, consistent with the quantitatively similar folding parameters observed either in the absence or presence of the ⌬F508 mutation. Login to comment

[hide] Side chain and backbone contributions of Phe508 to... Nat Struct Mol Biol. 2005 Jan;12(1):10-6. Epub 2004 Dec 26. Thibodeau PH, Brautigam CA, Machius M, Thomas PJ
Side chain and backbone contributions of Phe508 to CFTR folding.
Nat Struct Mol Biol. 2005 Jan;12(1):10-6. Epub 2004 Dec 26., [PMID:15619636]

Abstract [show]
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an integral membrane protein, cause cystic fibrosis (CF). The most common CF-causing mutant, deletion of Phe508, fails to properly fold. To elucidate the role Phe508 plays in the folding of CFTR, missense mutations at this position were generated. Only one missense mutation had a pronounced effect on the stability and folding of the isolated domain in vitro. In contrast, many substitutions, including those of charged and bulky residues, disrupted folding of full-length CFTR in cells. Structures of two mutant nucleotide-binding domains (NBDs) reveal only local alterations of the surface near position 508. These results suggest that the peptide backbone plays a role in the proper folding of the domain, whereas the side chain plays a role in defining a surface of NBD1 that potentially interacts with other domains during the maturation of intact CFTR.

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33 The F508A,F508M,F508P,F508D,F508Q,F508R and F508S mutant proteins were more similar to the wild type than the ∆F508 protein in their temperature-dependence of refolding (Fig. 1b,c). Login to comment
43 The missense mutant proteins F508A, F508M,F508P,F508D,F508Q,F508R and F508S had similar ∆Gunfolding and m-values, 3.4-3.8 kcal mol-1 and 1.5-1.7 kcal mol-1 M-1 denaturant, respectively, highlighting the fact that changes in the bulk or chemical properties of the substituted side chain had little effect on the native-state stabilities of these domains as measured by denaturation with GuHCl (Table 1). Login to comment
46 How does the isolated NBD accommodate such Temperature (ºC) 4 10 16 22 Fractionalyield 0.0 0.5 1.0 Temperature (ºC) 4 10 16 22 Temperature (ºC) 4 10 16 22 Wild type ∆F508 Wild type ∆F508 ̄ F508A ̄ F508M F508P F508W ͷ F508W W496F Wild type ∆F508 F508Q F508R F508D F508S a b c Figure 1 NBD1 folding efficiency as a function of folding temperature. Login to comment
53 Table 1 Stability of wild-type and mutant NBD proteins Protein ∆Gunfolding ∆∆Gunfolding m-value (kcal mol-1) (kcal mol-1) (kcal mol-1 M-1) Wild type 3.7 ± 0.1 0 1.7 ∆F508 3.6 ± 0.1 0.1 1.7 F508A 3.6 ± 0.2 0.1 1.6 F508M 3.5 ± 0.1 0.1 1.6 F508P 3.5 ± 0.3 0.2 1.6 F508D 3.6 ± 0.1 0.1 1.6 F508Q 3.5 ± 0.2 0.2 1.6 F508R 3.4 ± 0.3 0.3 1.6 F508S 3.8 ± 0.2 -0.1 1.6 considerable changes in amino acid character at position 508 when this position is critical to the proper biogenesis of the full-length protein, and what are the underlying structural changes associated with these substitutions? Login to comment
91 Band C levels in F508A, F508G, F508L and F508V as well as the polar amino acid substitutions F508S, F508T, F508N and F508Q were evident, but substantially reduced relative to wild-type band C levels. Login to comment
113 W ild type ∆∆F508 F508 F508D F508K F508E F508R F508H F508S F508T F508N F508Q C B Charged Polar F508A F508C F508I F508L ∆F508 F508 W ild type C B F508W F508Y F508G F508P Hydrophobic F508M F508V ̅̆ ̆ ̅ Figure 3 Maturation of full-length CFTR mutants. Login to comment
148 Note added in proof: Crystal structures of the human F508A missense NBD1 (with solublizing mutations F429S and H667R) and the corrected ∆F508 NBD1 (with three known suppressor mutations G550E, R553Q and R555K, and the solublizing mutations F409L, F429S, F433L and H667R) have been reported51. Login to comment
150 The in vivo yield of soluble ∆F508 protein is decreased relative to both the wild-type and F508A proteins with both solublizing and suppressor mutations, consistent with a decrease in the efficiency of domain folding as described in this study. Login to comment

[hide] The two ATP binding sites of cystic fibrosis trans... J Gen Physiol. 2006 Oct;128(4):413-22. Epub 2006 Sep 11. Zhou Z, Wang X, Liu HY, Zou X, Li M, Hwang TC
The two ATP binding sites of cystic fibrosis transmembrane conductance regulator (CFTR) play distinct roles in gating kinetics and energetics.
J Gen Physiol. 2006 Oct;128(4):413-22. Epub 2006 Sep 11., [PMID:16966475]

Abstract [show]
Cystic fibrosis transmembrane conductance regulator (CFTR), a member of the ABC (ATP binding cassette) transporter family, is a chloride channel whose activity is controlled by protein kinase-dependent phosphorylation. Opening and closing (gating) of the phosphorylated CFTR is coupled to ATP binding and hydrolysis at CFTR's two nucleotide binding domains (NBD1 and NBD2). Recent studies present evidence that the open channel conformation reflects a head-to-tail dimerization of CFTR's two NBDs as seen in the NBDs of other ABC transporters (Vergani et al., 2005). Whether these two ATP binding sites play an equivalent role in the dynamics of NBD dimerization, and thus in gating CFTR channels, remains unsettled. Based on the crystal structures of NBDs, sequence alignment, and homology modeling, we have identified two critical aromatic amino acids (W401 in NBD1 and Y1219 in NBD2) that coordinate the adenine ring of the bound ATP. Conversion of the W401 residue to glycine (W401G) has little effect on the sensitivity of the opening rate to [ATP], but the same mutation at the Y1219 residue dramatically lowers the apparent affinity for ATP by >50-fold, suggesting distinct roles of these two ATP binding sites in channel opening. The W401G mutation, however, shortens the open time constant. Energetic analysis of our data suggests that the free energy of ATP binding at NBD1, but not at NBD2, contributes significantly to the energetics of the open state. This kinetic and energetic asymmetry of CFTR's two NBDs suggests an asymmetric motion of the NBDs during channel gating. Opening of the channel is initiated by ATP binding at the NBD2 site, whereas separation of the NBD dimer at the NBD1 site constitutes the rate-limiting step in channel closing.

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61 The crystal structure of human F508A NBD1-ATP complexes (pdb code: 1xmi, chain A) was used as a template. Login to comment
81 (A) Interactions between ATP and key amino acids in the NBD1 binding pocket, adopted from the monomeric crystal structure of the human F508A NBD1-ATP complexes (pdb code: 1xmi, chain A) (left). Login to comment

[hide] In vivo phosphorylation of CFTR promotes formation... EMBO J. 2006 Oct 18;25(20):4728-39. Epub 2006 Oct 12. Mense M, Vergani P, White DM, Altberg G, Nairn AC, Gadsby DC
In vivo phosphorylation of CFTR promotes formation of a nucleotide-binding domain heterodimer.
EMBO J. 2006 Oct 18;25(20):4728-39. Epub 2006 Oct 12., 2006-10-18 [PMID:17036051]

Abstract [show]
The human ATP-binding cassette (ABC) protein CFTR (cystic fibrosis transmembrane conductance regulator) is a chloride channel, whose dysfunction causes cystic fibrosis. To gain structural insight into the dynamic interaction between CFTR's nucleotide-binding domains (NBDs) proposed to underlie channel gating, we introduced target cysteines into the NBDs, expressed the channels in Xenopus oocytes, and used in vivo sulfhydryl-specific crosslinking to directly examine the cysteines' proximity. We tested five cysteine pairs, each comprising one introduced cysteine in the NH(2)-terminal NBD1 and another in the COOH-terminal NBD2. Identification of crosslinked product was facilitated by co-expression of NH(2)-terminal and COOH-terminal CFTR half channels each containing one NBD. The COOH-terminal half channel lacked all native cysteines. None of CFTR's 18 native cysteines was found essential for wild type-like, phosphorylation- and ATP-dependent, channel gating. The observed crosslinks demonstrate that NBD1 and NBD2 interact in a head-to-tail configuration analogous to that in homodimeric crystal structures of nucleotide-bound prokaryotic NBDs. CFTR phosphorylation by PKA strongly promoted both crosslinking and opening of the split channels, firmly linking head-to-tail NBD1-NBD2 association to channel opening.

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41 Introduction of target cysteines for crosslinking studies On the basis of crystal structures of nucleotide-bound prokaryotic NBD homodimers and of monomeric NBD1 F508A from human CFTR, we made a homology model of the anticipated CFTR NBD1-NBD2 complex (Figure 3; see Materials and methods). Login to comment
55 NNBD1 NBD2 A462 S605 S1347 S459 S434 D1336 V1379 A1374 S549 S1248 Figure 3 Homology model of a head-to-tail CFTR NBD1-NBD2 heterodimer, based on crystal structures of human CFTR NBD1 F508A and of ATPor AMPPNP-bound NBDs of other ABC proteins (Materials and methods). Login to comment
220 Structural alignments were created including only ATP- (or AMPPNP-) bound NBD structures (HisP, PDB ID 1B0U (Hung et al, 1998); MJ0796, 1L2T (Smith et al, 2002); MalK, 1Q12 (Chen et al, 2003); GlcV, 1OXV (Verdon et al, 2003) and HlyB, 1XEF (Zaitseva et al, 2005), as well as human CFTR NBD1 F508A, 1XMI (Lewis et al, 2005). Login to comment

[hide] Building an understanding of cystic fibrosis on th... J Bioenerg Biomembr. 2007 Dec;39(5-6):499-505. Mendoza JL, Thomas PJ
Building an understanding of cystic fibrosis on the foundation of ABC transporter structures.
J Bioenerg Biomembr. 2007 Dec;39(5-6):499-505., [PMID:18080175]

Abstract [show]
Cystic fibrosis (CF) is a fatal disease affecting the lungs and digestive system by impairment of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). While over 1000 mutations in CFTR have been associated with CF, the majority of cases are linked to the deletion of phenylalanine 508 (delta F508). F508 is located in the first nucleotide binding domain (NBD1) of CFTR. This mutation is sufficient to impair the trafficking of CFTR to the plasma membrane and, thus, its function. As an ABC transporter, recent structural data from the family provide a framework on which to consider the effect of the delta F508 mutation on CFTR. There are fifty-seven known structures of ABC transporters and domains thereof. Only six of these structures are of the intact transporters. In addition, modern bioinformatic tools provide a wealth of sequence and structural information on the family. We will review the structural information from the RCSB structure repository and sequence databases of the ABC transporters. The available structural information was used to construct a model for CFTR based on the ABC transporter homologue, Sav1866, and provide a context for understanding the molecular pathology of Cystic Fibrosis.

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67 In contrast to the large number of sequences available for the NBD align- Table 1 ABC transporter structures in the research collaboratory for structural bioinformatics (RCSB) database Release Date PDB Protein Resolution Species NBD Structures Jun-05 1Z47 CysA 1.9 Alicyclobacillus acidocaldarius Sep-03 1OXX GlcV G144A 1.45 Sulfolobus solfataricus Jun-03 1OXT GlcV nucleotide free 2.1 Sulfolobus solfataricus Jun-03 1OXU GlcV w/ ADP 2.1 Sulfolobus solfataricus Jun-03 1OXV GlcV w/ AMP.PNP 2.1 Sulfolobus solfataricus Jun-03 1OXS GlcV w/ iodide ions 1.65 Sulfolobus solfataricus Nov-99 1B0U HisP w/ ATP 1.5 Salmonella typimurium Jun-03 1MT0 HlyB (467-707) 2.6 Escherichia coli Aug-06 2FFB HlyB E631Q w/ ADP 1.9 Escherichia coli Aug-06 2FGK HlyB E631Q w/ ATP 2.7 Escherichia coli Aug-06 2FFA HlyB H662A w/ ADP 1.7 Escherichia coli Aug-06 2FGJ HlyB H662A w/ ATP 2.6 Escherichia coli Jun-05 1XEF HlyB w/ ATP 2.5 Escherichia coli Aug-06 2FF7 HlyB w/ADP 1.6 Escherichia coli Dec-03 1MV5 LmrA w/ ADP, ATP 3.1 Lactococcus lactis Dec-00 1G29 MalK 1.9 Thermococcus litoralis Sep-03 1Q1E MalK 2.9 Escherichia coli Dec-04 1VCI MalK w/ ATP 2.9 Pyrococcus horikoshii Aug-07 2QRR metN 1.71 Vibrio parahaemolyticus Aug-07 2QSW metN C-terminal domain 1.5 Enterococcus faecalis Jul-02 1L2T MJ0796 E171Q Dimeric Structure 1.9 Methanococcus jannaschii Jul-01 1F3O MJ0796 w/ ADP 2.7 Methanococcus jannaschii Nov-01 1GAJ MJ1267 2.5 Methanococcus jannaschii Jul-01 1G6H MJ1267 w/ ADP 1.6 Methanococcus jannaschii Feb-03 1G9X MJ1267 w/ ADP 2.6 Methanococcus jannaschii May-06 2CBZ MRP1-NBD1 1.5 Homo sapiens Nov-04 1V43 Multi-sugar transporter 2.2 Pyrococcus horikoshii Aug-04 1SGW Putative 1.7 Pyrococcus furiosus Apr-07 2P0S Putative 1.6 Porphyromonas gingivalis Sep-07 2IHY Putative 1.9 Staphylococcus aureus Jan-06 2D3W SufC 2.5 Escherichia coli Oct-06 2IXE Tap1 D645N w/ ATP 2 Rattus norvegicus Oct-06 2IXF Tap1 D645Q, Q678H w/ ATP 2 Rattus norvegicus Oct-06 2IXG Tap1 S621A, G622V, D645N w/ ATP 2.7 Homo sapiens Sep-01 1JJ7 Tap1 w/ ADP 2.4 Homo sapiens Aug-02 1JI0 Thermatoga w/ ATP 2 Sulfolobus solfataricus Nov-04 1VPL TM0544 2.1 Thermotoga maritima CFTR NBD Structures Nov-04 1XMJ Human CFTR dF508 NBD1 2.3 Homo sapiens Nov-05 2BBT Human CFTR dF508 NBD1 w/ two solublizing mutations 2.3 Homo sapiens Nov-05 2BBS Human CFTR dF508 NBD1 w/ 3M 2.05 Homo sapiens Nov-05 2BBO Human CFTR NBD1 2.55 Homo sapiens Nov-04 1XMI Human CFTR NBD1-F508A w/ ATP 2.25 Homo sapiens Dec-04 1XFA Murine CFTR-F508R 3.1 Mus musculus Dec-04 1XF9 Murine CFTR-F508S 2.7 Mus musculus Dec-03 1R0W Murine CFTR NBD1 2.2 Mus musculus Dec-03 1R0Z Murine CFTR NBD1 - phosphorylated w/ ATP 2.35 Mus musculus J Bioenerg Biomembr (2007) 39:499-505 501501 ments in Pfam, only 6,419 transmembrane sequences are in the MSA of ABC transporter TMDs, PF00664 (Sonnhammer et al. 1997). Login to comment

[hide] Diminished self-chaperoning activity of the DeltaF... PLoS Comput Biol. 2008 Feb 29;4(2):e1000008. Serohijos AW, Hegedus T, Riordan JR, Dokholyan NV
Diminished self-chaperoning activity of the DeltaF508 mutant of CFTR results in protein misfolding.
PLoS Comput Biol. 2008 Feb 29;4(2):e1000008., [PMID:18463704]

Abstract [show]
The absence of a functional ATP Binding Cassette (ABC) protein called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) from apical membranes of epithelial cells is responsible for cystic fibrosis (CF). Over 90% of CF patients carry at least one mutant allele with deletion of phenylalanine at position 508 located in the N-terminal nucleotide binding domain (NBD1). Biochemical and cell biological studies show that the DeltaF508 mutant exhibits inefficient biosynthetic maturation and susceptibility to degradation probably due to misfolding of NBD1 and the resultant misassembly of other domains. However, little is known about the direct effect of the Phe508 deletion on the NBD1 folding, which is essential for rational design strategies of cystic fibrosis treatment. Here we show that the deletion of Phe508 alters the folding dynamics and kinetics of NBD1, thus possibly affecting the assembly of the complete CFTR. Using molecular dynamics simulations, we find that meta-stable intermediate states appearing on wild type and mutant folding pathways are populated differently and that their kinetic accessibilities are distinct. The structural basis of the increased misfolding propensity of the DeltaF508 NBD1 mutant is the perturbation of interactions in residue pairs Q493/P574 and F575/F578 found in loop S7-H6. As a proof-of-principle that the S7-H6 loop conformation can modulate the folding kinetics of NBD1, we virtually design rescue mutations in the identified critical interactions to force the S7-H6 loop into the wild type conformation. Two redesigned NBD1-DeltaF508 variants exhibited significantly higher folding probabilities than the original NBD1-DeltaF508, thereby partially rescuing folding ability of the NBD1-DeltaF508 mutant. We propose that these observed defects in folding kinetics of mutant NBD1 may also be modulated by structures separate from the 508 site. The identified structural determinants of increased misfolding propensity of NBD1-DeltaF508 are essential information in correcting this pathogenic mutant.

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48 We also perform simulations of another mutant NBD1-F508A to serve as control. Login to comment
62 Thermodynamics of NBD1-WT, NBD1-F508A, and NBD1-DF508. Login to comment
63 Energy is calculated from long equilibrium simulations (106 time units) of NBD1-WT, NBD1-F508A, and NBD1-DF508 crystal structures. Login to comment
70 Here, using molecular dynamics simulations of NBD1-WT, NBD1-F508A, and NBD1-DF508, we show that the deletion of Phe508 indeed alters the kinetics of NBD1 folding. Login to comment
81 Folding simulations of our control structure NBD1-F508A yield a folding probability of 2664% which is intermediate to that NBD1-WTand NBD1-DF508. Login to comment
82 This folding probability value is in agreement with experimental studies showing intermediate folding efficiencies and maturation levels of NBD1-F508A relative to NBD1-WT [9,11]. Login to comment
83 To investigate the molecular origin of the difference in folding yields and probabilities, we map the folding pathways of NBD1-WT, NBD1-F508A, and NBD1-DF508 by identifying their metastable folding intermediate states. Login to comment
92 Folding Pathways To determine the difference between the sequence of folding events of the wild type, DF508, and the F508A control, we estimate the probability of transitions between intermediate states (see Methods and Figure S3). Login to comment
93 The difference in transition probabilities of NBD1-WT, NBD1-DF508, and NBD1-F508A is shown in Figure 4. Login to comment
127 Crystal structures of NBD1-WT, NBD1-F508A, and NBD1DF508 are also practically identical except for the S7-H6 loop (Figure 1B) [9,10,12]. Login to comment
131 U S10 S9 S8 S7 S6 S5 S4 S3 S2 S1 U S10 S9 S8 S7 S5 S4 S3 S2 S1 A B 0.65 0.85 0.64 0.94 0.79 0.1 0.91 0.13 0.15 0.15 0.13 0.11 0.2 0.15 0.76 0.19 0.1 0.57 0.58 0.14 0.69 0.1 0.64 0.93 0.14 0.91 0.9 0.1 0.15 0.84 0.25 0.15 0.23 0.31 0.16 0.9 0.15 NBD1-F508A vs. NBD1-WT NBD1-∆F508 vs. NBD1-WT Figure 4. Login to comment
147 A relevant control of our simulation protocol and modeling assumptions is the folding simulation of the NBD1-F508A that yields a folding probability of 2664%, which is higher than that of NBD1DF08 but lower than that of NBD1-WT. Login to comment
173 The nuanced effect of a mutation or deletion at position 508 is already reflected in the S7-H6 loop conformation of NBD1-WT, NBD1-F508A, and NBD1DF508 crystal structures. Login to comment
199 Contacts in NBD1-WT that perturbed in the F508A and DF508 mutants. Login to comment
211 Folding Simulations We perform 300 folding simulations for each NBD1-WT, NBD1-F508A, and NBD1-DF508. Login to comment
237 Probability of kinetic transitions between intermediate states of NBD1-WT, NBD1-DF508, and NBD1-F508A. Login to comment

[hide] Relationship between nucleotide binding and ion ch... J Physiol. 2009 Jun 15;587(Pt 12):2875-86. Epub 2009 Apr 29. Aleksandrov AA, Cui L, Riordan JR
Relationship between nucleotide binding and ion channel gating in cystic fibrosis transmembrane conductance regulator.
J Physiol. 2009 Jun 15;587(Pt 12):2875-86. Epub 2009 Apr 29., 2009-06-15 [PMID:19403599]

Abstract [show]
We have employed rate-equilibrium free energy relationship (REFER) analysis to characterize the dynamic events involved in the allosteric regulation of cystic fibrosis transmembrane conductance regulator (CFTR) function. A wide range of different hydrolysable and poorly hydrolysable nucleoside triphosphates were used to elucidate the role of ATP hydrolysis in CFTR function. The linearity of the REFER plots and Phi values near unity for all ligands tested implies that CFTR channel gating is a reversible thermally driven process with all structural reorganization in the binding site(s) completed prior to channel opening. This is consistent with the requirement for nucleotide binding for channel opening. However, the channel structural transition from the open to the closed state occurs independently of any events in the binding sites. Similar results were obtained on substitution of amino acids at coupling joints between both nucleotide binding domains (NBD) and cytoplasmic loops (CL) in opposite halves of the protein, indicating that any structural reorganization there also had occurred in the channel closed state. The fact that fractional Phi values were not observed in either of these distant sites suggests that there may not be a deterministic 'lever-arm' mechanism acting between nucleotide binding sites and the channel gate. These findings favour a stochastic coupling between binding and gating in which all structural transitions are thermally driven processes. We speculate that increase of channel open state probability is due to reduction of the number of the closed state configurations available after physical interaction between ligand bound NBDs and the channel.

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136 All mutants have nearly the same mean open time of 220 ms while mean closed times varied from 230 ms for the wild-type CFTR to 7.8 s for F508A. Login to comment

[hide] NMR evidence for differential phosphorylation-depe... EMBO J. 2010 Jan 6;29(1):263-77. Epub 2009 Nov 19. Kanelis V, Hudson RP, Thibodeau PH, Thomas PJ, Forman-Kay JD
NMR evidence for differential phosphorylation-dependent interactions in WT and DeltaF508 CFTR.
EMBO J. 2010 Jan 6;29(1):263-77. Epub 2009 Nov 19., 2010-01-06 [PMID:19927121]

Abstract [show]
The most common cystic fibrosis (CF)-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is deletion of Phe508 (DeltaF508) in the first of two nucleotide-binding domains (NBDs). Nucleotide binding and hydrolysis at the NBDs and phosphorylation of the regulatory (R) region are required for gating of CFTR chloride channel activity. We report NMR studies of wild-type and DeltaF508 murine CFTR NBD1 with the C-terminal regulatory extension (RE), which contains residues of the R region. Interactions of the wild-type NBD1 core with the phosphoregulatory regions, the regulatory insertion (RI) and RE, are disrupted upon phosphorylation, exposing a potential binding site for the first coupling helix of the N-terminal intracellular domain (ICD). Phosphorylation of DeltaF508 NBD1 does not as effectively disrupt interactions with the phosphoregulatory regions, which, along with other structural differences, leads to decreased binding of the first coupling helix. These results provide a structural basis by which phosphorylation of CFTR may affect the channel gating of full-length CFTR and expand our understanding of the molecular basis of the DeltaF508 defect.

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96 This surface changes when the RE adopts an alternate conformation and contacts only helices H6 and H7, as observed in the crystal structure of human NBD1-RE F508A (Lewis et al, 2004, 2005). Login to comment
179 The crystal structure of the human F508A NBD1-RE (Lewis et al, 2005), in which the RI is not bound to the NBD core, was also used as a template. Login to comment
191 This interface is occluded in crystal structures of the murine WT and human DF508 NBD1-RE in which the RI is bound to the NBD core, but is exposed in the human F508A NBD1-RE structure (Lewis et al, 2004, 2005). Login to comment
234 Notably, a 1801 rotation in position of the RE and RI between the murine WT and human F508A crystal structures (Lewis et al, 2004, 2005) (Supplementary Figure 1b) also indicates significant conformational flexibility of the phospho-regulatory elements of CFTR. Login to comment
310 The crystal structures of Sav1866 (PDB code 2HYD) and the human CFTR F508A NBD1-RE (PDB code 1XMI), excluding residues Gln634-Asp673, were used as templates. Login to comment

[hide] Structure and dynamics of NBD1 from CFTR character... J Mol Biol. 2010 Feb 19;396(2):406-30. Epub 2009 Nov 26. Lewis HA, Wang C, Zhao X, Hamuro Y, Conners K, Kearins MC, Lu F, Sauder JM, Molnar KS, Coales SJ, Maloney PC, Guggino WB, Wetmore DR, Weber PC, Hunt JF
Structure and dynamics of NBD1 from CFTR characterized using crystallography and hydrogen/deuterium exchange mass spectrometry.
J Mol Biol. 2010 Feb 19;396(2):406-30. Epub 2009 Nov 26., 2010-02-19 [PMID:19944699]

Abstract [show]
The DeltaF508 mutation in nucleotide-binding domain 1 (NBD1) of the cystic fibrosis transmembrane conductance regulator (CFTR) is the predominant cause of cystic fibrosis. Previous biophysical studies on human F508 and DeltaF508 domains showed only local structural changes restricted to residues 509-511 and only minor differences in folding rate and stability. These results were remarkable because DeltaF508 was widely assumed to perturb domain folding based on the fact that it prevents trafficking of CFTR out of the endoplasmic reticulum. However, the previously reported crystal structures did not come from matched F508 and DeltaF508 constructs, and the DeltaF508 structure contained additional mutations that were required to obtain sufficient protein solubility. In this article, we present additional biophysical studies of NBD1 designed to address these ambiguities. Mass spectral measurements of backbone amide (1)H/(2)H exchange rates in matched F508 and DeltaF508 constructs reveal that DeltaF508 increases backbone dynamics at residues 509-511 and the adjacent protein segments but not elsewhere in NBD1. These measurements also confirm a high level of flexibility in the protein segments exhibiting variable conformations in the crystal structures. We additionally present crystal structures of a broader set of human NBD1 constructs, including one harboring the native F508 residue and others harboring the DeltaF508 mutation in the presence of fewer and different solubilizing mutations. The only consistent conformational difference is observed at residues 509-511. The side chain of residue V510 in this loop is mostly buried in all non-DeltaF508 structures but completely solvent exposed in all DeltaF508 structures. These results reinforce the importance of the perturbation DeltaF508 causes in the surface topography of NBD1 in a region likely to mediate contact with the transmembrane domains of CFTR. However, they also suggest that increased exposure of the 509-511 loop and increased dynamics in its vicinity could promote aggregation in vitro and aberrant intermolecular interactions that impede trafficking in vivo.

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114 Taking this possibility into account, the available structures can be clustered into three maximally independent groups-the four hNBD1 structures from crystals grown in high-molecular-weight PEG precipitants at pH ~7.5-9.0 (1XMJ, 2BBO, 2BBS, and 2BBT), the single hNBD1-F508A structure from a crystal grown in a low-molecular-weight PEG precipitant at pH ~4.5 (1XMI), and the nine mNBD1 structures from crystals grown using 3.5 M sodium acetate as the precipitant at pH 7.5. Login to comment
132 Bright green and magenta represent human F508 and F508A structures, respectively, shades of red/orange represent human ΔF508 human structures, and shades of blue/cyan represent murine structures (F508, F508S, or F508R). Login to comment
156 Other than these variations in domain orientation and loop conformation, no significant structural variations are observed elsewhere even in the most divergent structures in the ensemble (PDB IDs 1XMI and 1R0Z, containing hNBD1-2b-F508A and mNBD1, respectively). Login to comment

[hide] Structures of a minimal human CFTR first nucleotid... Protein Eng Des Sel. 2010 May;23(5):375-84. Epub 2010 Feb 11. Atwell S, Brouillette CG, Conners K, Emtage S, Gheyi T, Guggino WB, Hendle J, Hunt JF, Lewis HA, Lu F, Protasevich II, Rodgers LA, Romero R, Wasserman SR, Weber PC, Wetmore D, Zhang FF, Zhao X
Structures of a minimal human CFTR first nucleotide-binding domain as a monomer, head-to-tail homodimer, and pathogenic mutant.
Protein Eng Des Sel. 2010 May;23(5):375-84. Epub 2010 Feb 11., [PMID:20150177]

Abstract [show]
Upon removal of the regulatory insert (RI), the first nucleotide binding domain (NBD1) of human cystic fibrosis transmembrane conductance regulator (CFTR) can be heterologously expressed and purified in a form that remains stable without solubilizing mutations, stabilizing agents or the regulatory extension (RE). This protein, NBD1 387-646(Delta405-436), crystallizes as a homodimer with a head-to-tail association equivalent to the active conformation observed for NBDs from symmetric ATP transporters. The 1.7-A resolution X-ray structure shows how ATP occupies the signature LSGGQ half-site in CFTR NBD1. The DeltaF508 version of this protein also crystallizes as a homodimer and differs from the wild-type structure only in the vicinity of the disease-causing F508 deletion. A slightly longer construct crystallizes as a monomer. Comparisons of the homodimer structure with this and previously published monomeric structures show that the main effect of ATP binding at the signature site is to order the residues immediately preceding the signature sequence, residues 542-547, in a conformation compatible with nucleotide binding. These residues likely interact with a transmembrane domain intracellular loop in the full-length CFTR channel. The experiments described here show that removing the RI from NBD1 converts it into a well-behaved protein amenable to biophysical studies yielding deeper insights into CFTR function.

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207 A similar analysis has been conducted comparing a human DF508 NBD1 with a human F508A NBD1 with different sets of solubilizing mutations (Lewis et al., 2005). Login to comment

[hide] The cystic fibrosis-causing mutation deltaF508 aff... J Biol Chem. 2010 Nov 12;285(46):35825-35. Epub 2010 Jul 28. Thibodeau PH, Richardson JM 3rd, Wang W, Millen L, Watson J, Mendoza JL, Du K, Fischman S, Senderowitz H, Lukacs GL, Kirk K, Thomas PJ
The cystic fibrosis-causing mutation deltaF508 affects multiple steps in cystic fibrosis transmembrane conductance regulator biogenesis.
J Biol Chem. 2010 Nov 12;285(46):35825-35. Epub 2010 Jul 28., 2010-11-12 [PMID:20667826]

Abstract [show]
The deletion of phenylalanine 508 in the first nucleotide binding domain of the cystic fibrosis transmembrane conductance regulator is directly associated with >90% of cystic fibrosis cases. This mutant protein fails to traffic out of the endoplasmic reticulum and is subsequently degraded by the proteasome. The effects of this mutation may be partially reversed by the application of exogenous osmolytes, expression at low temperature, and the introduction of second site suppressor mutations. However, the specific steps of folding and assembly of full-length cystic fibrosis transmembrane conductance regulator (CFTR) directly altered by the disease-causing mutation are unclear. To elucidate the effects of the DeltaF508 mutation, on various steps in CFTR folding, a series of misfolding and suppressor mutations in the nucleotide binding and transmembrane domains were evaluated for effects on the folding and maturation of the protein. The results indicate that the isolated NBD1 responds to both the DeltaF508 mutation and intradomain suppressors of this mutation. In addition, identification of a novel second site suppressor of the defect within the second transmembrane domain suggests that DeltaF508 also effects interdomain interactions critical for later steps in the biosynthesis of CFTR.

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115 Consistent with this result, the introduction of the -3M mutations onto F508A and F508C had little effect on protein maturation. Login to comment

[hide] Small molecule correctors of F508del-CFTR discover... J Comput Aided Mol Des. 2010 Dec;24(12):971-91. Epub 2010 Oct 26. Kalid O, Mense M, Fischman S, Shitrit A, Bihler H, Ben-Zeev E, Schutz N, Pedemonte N, Thomas PJ, Bridges RJ, Wetmore DR, Marantz Y, Senderowitz H
Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening.
J Comput Aided Mol Des. 2010 Dec;24(12):971-91. Epub 2010 Oct 26., [PMID:20976528]

Abstract [show]
Folding correctors of F508del-CFTR were discovered by in silico structure-based screening utilizing homology models of CFTR. The intracellular segment of CFTR was modeled and three cavities were identified at inter-domain interfaces: (1) Interface between the two Nucleotide Binding Domains (NBDs); (2) Interface between NBD1 and Intracellular Loop (ICL) 4, in the region of the F508 deletion; (3) multi-domain interface between NBD1:2:ICL1:2:4. We hypothesized that compounds binding at these interfaces may improve the stability of the protein, potentially affecting the folding yield or surface stability. In silico structure-based screening was performed at the putative binding-sites and a total of 496 candidate compounds from all three sites were tested in functional assays. A total of 15 compounds, representing diverse chemotypes, were identified as F508del folding correctors. This corresponds to a 3% hit rate, ~tenfold higher than hit rates obtained in corresponding high-throughput screening campaigns. The same binding sites also yielded potentiators and, most notably, compounds with a dual corrector-potentiator activity (dual-acting). Compounds harboring both activity types may prove to be better leads for the development of CF therapeutics than either pure correctors or pure potentiators. To the best of our knowledge this is the first report of structure-based discovery of CFTR modulators.

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255 Solubilizing mutations and the F508A mutation present in 1XMI were mutated back to the wild-type sequence using Prime [48]. Login to comment

[hide] Molecular modeling tools and approaches for CFTR a... Methods Mol Biol. 2011;741:347-63. Serohijos AW, Thibodeau PH, Dokholyan NV
Molecular modeling tools and approaches for CFTR and cystic fibrosis.
Methods Mol Biol. 2011;741:347-63., [PMID:21594796]

Abstract [show]
Cystic fibrosis is a multi-faceted disease resulting from the dysfunction of the CFTR channel. Understanding the structural basis of channel function and the structural origin of the defect is imperative in the development of therapeutic strategies. Here, we describe molecular modeling tools that, in conjunction with complementary experimental tools, lead to significant findings on CFTR channel function and on the effect of the pathogenic mutant F508del.

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112 We used the following structures for wild type and mutant NBD1s: wild type (PDB ID: 2BBO), F508del (PDB ID: 1XMJ), and F508A (PDB ID: 1XMI) (see Note 2). Login to comment
113 The F508A mutant has been shown to exhibit intermediate folding defects compared to F508del (7), and thus is an interesting control for the folding simulations. Login to comment
124 Simulation Protocol Using the simplified models described above, in our previous studies, we performed folding simulations for each NBD1-WT, NBD1-F508del, and NBD1-F508A. Login to comment
135 (c) Contacts in NBD1-WT that perturbed in the F508A and F508del mutants. Login to comment
150 We found that at the given tmax, wild type exhibited higher folding probability than the F508del, and F508A folding probability is intermediate to that of wild type and F508del. Login to comment

[hide] Modelling the restoration of wild-type dynamic beh... J Mol Graph Model. 2007 Oct;26(3):691-9. Epub 2007 Apr 24. Warner DJ, Vadolia MM, Laughton CA, Kerr ID, Doughty SW
Modelling the restoration of wild-type dynamic behaviour in DeltaF508-CFTR NBD1 by 8-cyclopentyl-1,3-dipropylxanthine.
J Mol Graph Model. 2007 Oct;26(3):691-9. Epub 2007 Apr 24., [PMID:17531517]

Abstract [show]
Cystic fibrosis (CF) is the most frequently occurring severe, genetic disease in western populations with an incidence as high as 1 in 2500. The principal biochemical defect in CF is a mutation in a membrane transport protein, namely the cystic fibrosis transmembrane conductance regulator (CFTR), which is responsible for the conductance of chloride ions across cell membranes. In 70% of cases a single mutation in CFTR, namely the deletion of amino acid 508 (called DeltaF508) is sufficient to cause severe disease. This mutation manifests as a failure of the protein to be effectively targeted to the membrane. Recently, it has been shown that small molecule drug therapy can restore the membrane-targeting of DeltaF508-CFTR, where the mutant channel functions adequately. We have created models of the first nucleotide-binding domain (NBD1) region (which houses the proposed binding site of these restorative drugs) of the wild-type and mutant forms of human CFTR. We have simulated the dynamical behaviour of these proteins in the presence of drugs that restore trafficking of the protein. Our results indicate that there are particular modes of dynamic motion that are distinguishable between wild-type and mutant CFTR. These regions of motion are localized in the regions of the DeltaF508 mutation and the drug-binding regions. The simulations of drug binding indicate that wild-type dynamic motions are restored in these regions. We conclude therefore that these drugs are able to alter the dynamic properties of DeltaF508-CFTR such that the drug-bound mutant protein more closely resembles the wild-type protein dynamic behaviour, and hence we hypothesize that it is this that allows for correct targeting to the membrane.

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55 Following completion of the work presented here, crystal structures for human CFTR DF508 and F508A NBD1 domains were reported and made available [22] (PDB codes 1XMI and 1XMJ). Login to comment

[hide] Molecular modelling approaches for cystic fibrosis... Int J Biochem Cell Biol. 2014 Jul;52:39-46. doi: 10.1016/j.biocel.2014.04.004. Epub 2014 Apr 13. Odolczyk N, Zielenkiewicz P
Molecular modelling approaches for cystic fibrosis transmembrane conductance regulator studies.
Int J Biochem Cell Biol. 2014 Jul;52:39-46. doi: 10.1016/j.biocel.2014.04.004. Epub 2014 Apr 13., [PMID:24735712]

Abstract [show]
Cystic fibrosis (CF) is one of the most common genetic disorders, caused by loss of function mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. CFTR is a member of ATP-binding cassette (ABC) transporters superfamily and functions as an ATP-gated anion channel. This review summarises the vast majority of the efforts which utilised molecular modelling approaches to gain insight into the various aspects of CFTR protein, related to its structure, dynamic properties, function and interactions with other protein partners, or drug-like compounds, with emphasis to its relation to CF disease.

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1804 The calculations were performed on simplified bead protein models of three NBD1 variants as follows: WT-NBD1, F508-NBD1 and F508A-NBD1. Login to comment