ABCC7 p.Arg134Glu
| Predicted by SNAP2: | A: D (75%), C: D (80%), D: D (91%), E: D (85%), F: D (85%), G: D (80%), H: D (75%), I: D (80%), K: D (59%), L: D (66%), M: D (80%), N: D (75%), P: D (91%), Q: D (71%), S: D (71%), T: D (71%), V: D (80%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: N, C: D, D: D, E: N, F: D, G: D, H: N, I: D, K: N, L: D, M: N, N: N, P: D, Q: N, S: N, T: D, V: D, W: D, Y: D, |
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[hide] New Model of Cystic Fibrosis Transmembrane Conduct... J Chem Inf Model. 2012 Jul 12. Dalton J, Kalid O, Schushan M, Ben-Tal N, Villa-Freixa J
New Model of Cystic Fibrosis Transmembrane Conductance Regulator Proposes Active Channel-like Conformation.
J Chem Inf Model. 2012 Jul 12., [PMID:22747419]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) is an unusual ABC transporter, functioning as a chloride channel critical for fluid homeostasis in multiple organs. Disruption of CFTR function is associated with cystic fibrosis making it an attractive therapeutic target. In addition, CFTR blockers are being developed as potential antidiarrheals. CFTR drug discovery is hampered by the lack of high resolution structural data, and considerable efforts have been invested in modeling the channel structure. Although previously published CFTR models that have been made publicly available mostly agree with experimental data relating to the overall structure, they present the channel in an outward-facing conformation that does not agree with expected properties of a "channel-like" structure. Here, we make available a model of CFTR in such a "channel-like" conformation, derived by a unique modeling approach combining restrained homology modeling and ROSETTA refinement. In contrast to others, the present model is in agreement with expected channel properties such as pore shape, dimensions, solvent accessibility, and experimentally derived distances. We have used the model to explore the interaction of open channel blockers within the pore, revealing a common binding mode and ionic interaction with K95, in agreement with experimental data. The binding-site was further validated using a virtual screening enrichment experiment, suggesting the model might be suitable for drug discovery. In addition, we subjected the model to a molecular dynamics simulation, revealing previously unaddressed salt-bridge interactions that may be important for structure stability and pore-lining residues that may take part in Cl(-) conductance.
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No. Sentence Comment
131 Notably, a salt bridge between R134 and E1104 is supported by the finding that R134E/Q mutations are detrimental to channel Figure 8.
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ABCC7 p.Arg134Glu 22747419:131:79
status: NEW[hide] Cystic Fibrosis Transmembrane Conductance Regulato... J Biol Chem. 2015 Sep 18;290(38):22891-906. doi: 10.1074/jbc.M115.665125. Epub 2015 Jul 30. Corradi V, Vergani P, Tieleman DP
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR): CLOSED AND OPEN STATE CHANNEL MODELS.
J Biol Chem. 2015 Sep 18;290(38):22891-906. doi: 10.1074/jbc.M115.665125. Epub 2015 Jul 30., [PMID:26229102]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette (ABC) transporter superfamily. CFTR controls the flow of anions through the apical membrane of epithelia. Dysfunctional CFTR causes the common lethal genetic disease cystic fibrosis. Transitions between open and closed states of CFTR are regulated by ATP binding and hydrolysis on the cytosolic nucleotide binding domains, which are coupled with the transmembrane (TM) domains forming the pathway for anion permeation. Lack of structural data hampers a global understanding of CFTR and thus the development of "rational" approaches directly targeting defective CFTR. In this work, we explored possible conformational states of the CFTR gating cycle by means of homology modeling. As templates, we used structures of homologous ABC transporters, namely TM(287-288), ABC-B10, McjD, and Sav1866. In the light of published experimental results, structural analysis of the transmembrane cavity suggests that the TM(287-288)-based CFTR model could correspond to a commonly occupied closed state, whereas the McjD-based model could represent an open state. The models capture the important role played by Phe-337 as a filter/gating residue and provide structural information on the conformational transition from closed to open channel.
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No. Sentence Comment
81 Additional distance restraints were also imposed to facilitate electrostatic interactions between residues (Arg-134-Glu-1104, Asp-873-Arg-933, and Arg-1102-Asp-1154) suggested to interact, based on the work of Dalton et al. (35).
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ABCC7 p.Arg134Glu 26229102:81:108
status: NEW