ABCC1 p.Lys684Arg
| Predicted by SNAP2: | A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: 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, F: D, G: D, H: D, I: 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] Functional interactions between nucleotide binding... Mol Pharmacol. 2005 Jun;67(6):1944-53. Epub 2005 Mar 8. Payen L, Gao M, Westlake C, Theis A, Cole SP, Deeley RG
Functional interactions between nucleotide binding domains and leukotriene C4 binding sites of multidrug resistance protein 1 (ABCC1).
Mol Pharmacol. 2005 Jun;67(6):1944-53. Epub 2005 Mar 8., [PMID:15755910]
Abstract [show]
Multidrug resistance protein 1 (MRP1) is a member of the "C" branch of the ATP-binding cassette transporter superfamily. The NH(2)-proximal nucleotide-binding domain (NBD1) of MRP1 differs functionally from its COOH-proximal domain (NBD2). NBD1 displays intrinsic high-affinity ATP binding and little ATPase activity. In contrast, ATP binding to NBD2 is strongly dependent on nucleotide binding by NBD1, and NBD2 is more hydrolytically active. We have demonstrated that occupancy of NBD2 by ATP or ADP markedly decreased substrate binding by MRP1. We have further explored the relationship between nucleotide and substrate binding by examining the effects of various ATP analogs and ADP trapping, as well as mutations in conserved functional elements in the NBDs, on the ability of MRP1 to bind the photoactivatable, high-affinity substrate cysteinyl leukotriene C(4) (LTC(4))(.) Overall, the results support a model in which occupancy of both NBD1 and NBD2 by ATP results in the formation of a low-affinity conformation of the protein. However, nonhydrolyzable ATP analogs (beta,gamma-imidoadenosine 5'-triphosphate and adenylylmethylene diphosphonate) failed to substitute for ATP or adenosine 5'-O-(thiotriphosphate) (ATPgammaS) in decreasing LTC(4) photolabeling. Furthermore, mutations of the signature sequence in either NBD that had no apparent effect on azido-ATP binding abrogated the formation of a low-affinity substrate binding state in the presence of ATP or ATPgammaS. We suggest that the effect of these mutations, and possibly the failure of some ATP analogs to decrease LTC(4) binding, may be attributable to an inability to elicit a conformational change in the NBDs that involves interactions between the signature sequence and the gamma-phosphate of the bound nucleotide.
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No. Sentence Comment
65 The forward primers for creating K684R, K684E, K1333R, and K1333E mutations of Walker A motifs were 5Ј-GGCTGCGGAAGGTCGTC- CCTGC-3Ј, 5Ј-GGGCTGCGGAGAGTCGTCCCTGC-3Ј, 5Ј-GGGAGC- TGGGAGGTCGTCCCTGA-3Ј, and 5Ј-GGGAGCTGGGGAGTCGTC- CCTGA-3Ј, respectively.
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ABCC1 p.Lys684Arg 15755910:65:33
status: NEW131 Densitometry of immunoblots of vesicle proteins indicated that levels of the K684R, K684E, K1333R, and K1333E MRP1 mutants ranged from 30 to 60% those of wt MRP1 (Fig. 3A).
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ABCC1 p.Lys684Arg 15755910:131:77
status: NEW133 It is noteworthy that the K684R substitution in NBD1 decreased ATP-dependent LTC4 uptake by only 40%, whereas the K1333R mutation in NBD2 reduced transport by approximately 80% (Fig. 2B).
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ABCC1 p.Lys684Arg 15755910:133:26
status: NEW158 Membrane vesicles (1 g of total protein) prepared from Sf21 cells expressing a combination of a wt and mutant half-molecule containing a K684E, K684R, K1333E, or K1333R mutation were separated by SDS-PAGE on gradient gels and transferred to Immobilon-P membranes.
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ABCC1 p.Lys684Arg 15755910:158:152
status: NEW163 The relative expression levels of wt and mutant proteins evaluated by densitometry are indicated in the figure. B, effect of K684E, K684R, K1333E, and K1333R mutations on ATP-dependent LTC4 transport activity.
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ABCC1 p.Lys684Arg 15755910:163:132
status: NEW175 The conservative K684R mutation also decreased photolabeling of both NBDs but to a lesser extent than either the aspartic acid or methionine mutations (Fig. 3C).
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ABCC1 p.Lys684Arg 15755910:175:17
status: NEW204 Membrane vesicles (50 g of total protein) containing wt and the K684R, K684E, K1333R, and K1333E mutant MRP1 half-molecules were incubated in transport buffer at 23°C for 20 min in the absence or presence of ATP␥S (4 mM) or ATP (1 mM) plus vanadate (1 mM) before the addition of [3 H]LTC4 (200 nM, 0.13 Ci).
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ABCC1 p.Lys684Arg 15755910:204:72
status: NEW[hide] Hydrogen-bond formation of the residue in H-loop o... Biochim Biophys Acta. 2007 Feb;1768(2):324-35. Epub 2006 Nov 18. Yang R, Chang XB
Hydrogen-bond formation of the residue in H-loop of the nucleotide binding domain 2 with the ATP in this site and/or other residues of multidrug resistance protein MRP1 plays a crucial role during ATP-dependent solute transport.
Biochim Biophys Acta. 2007 Feb;1768(2):324-35. Epub 2006 Nov 18., [PMID:17187755]
Abstract [show]
MRP1 couples ATP binding/hydrolysis to solute transport. We have shown that ATP binding to nucleotide-binding-domain 1 (NBD1) plays a regulatory role whereas ATP hydrolysis at NBD2 plays a crucial role in ATP-dependent solute transport. However, how ATP is hydrolyzed at NBD2 is not well elucidated. To partially address this question, we have mutated the histidine residue in H-loop of MRP1 to either a residue that prevents the formation of hydrogen-bonds with ATP and other residues in MRP1 or a residue that may potentially form these hydrogen-bonds. Interestingly, substitution of H827 in NBD1 with residues that prevented formation of these hydrogen-bonds had no effect on the ATP-dependent solute transport whereas corresponding mutations in NBD2 almost abolished the ATP-dependent solute transport completely. In contrast, substitutions of H1486 in H-loop of NBD2 with residues that might potentially form these hydrogen-bonds exerted either full function or partial function, implying that hydrogen-bond formation between the residue at 1486 and the gamma-phosphate of the bound ATP and/or other residues, such as putative catalytic base E1455, together with S769, G771, T1329 and K1333, etc., holds all the components necessary for ATP binding/hydrolysis firmly so that the activated water molecule can efficiently hydrolyze the bound ATP at NBD2.
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No. Sentence Comment
189 For example, ATP binding to wild-type MRP1 can transport the bound LTC4 from high to low affinity site whereas ATP binding to the K684R- or the D1454N-mutated MRP1 cannot [30].
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ABCC1 p.Lys684Arg 17187755:189:130
status: NEW[hide] A molecular understanding of ATP-dependent solute ... Cancer Metastasis Rev. 2007 Mar;26(1):15-37. Chang XB
A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1.
Cancer Metastasis Rev. 2007 Mar;26(1):15-37., [PMID:17295059]
Abstract [show]
Over a million new cases of cancers are diagnosed each year in the United States and over half of these patients die from these devastating diseases. Thus, cancers cause a major public health problem in the United States and worldwide. Chemotherapy remains the principal mode to treat many metastatic cancers. However, occurrence of cellular multidrug resistance (MDR) prevents efficient killing of cancer cells, leading to chemotherapeutic treatment failure. Numerous mechanisms of MDR exist in cancer cells, such as intrinsic or acquired MDR. Overexpression of ATP-binding cassette (ABC) drug transporters, such as P-glycoprotein (P-gp or ABCB1), breast cancer resistance protein (BCRP or ABCG2) and/or multidrug resistance-associated protein (MRP1 or ABCC1), confers an acquired MDR due to their capabilities of transporting a broad range of chemically diverse anticancer drugs. In addition to their roles in MDR, there is substantial evidence suggesting that these drug transporters have functions in tissue defense. Basically, these drug transporters are expressed in tissues important for absorption, such as in lung and gut, and for metabolism and elimination, such as in liver and kidney. In addition, these drug transporters play an important role in maintaining the barrier function of many tissues including blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier. Thus, these ATP-dependent drug transporters play an important role in the absorption, disposition and elimination of the structurally diverse array of the endobiotics and xenobiotics. In this review, the molecular mechanism of ATP-dependent solute transport by MRP1 will be addressed.
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No. Sentence Comment
241 Indeed, several mutations, such as K684E, K1333E, K684R, K1333R, D792N, D1454N, G771A and G1433A, significantly diminished ATP binding and Vi-dependent ADP trapping at NBD2 and lost the ability to shift the substrate binding from a high to low affinity site [61].
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ABCC1 p.Lys684Arg 17295059:241:50
status: NEW256 Mutation of the Walker A motif K684 residue in NBD1, such as K684L [40, 141, 148], K684M [16, 63, 118], K684R [61] or K684E [61], significantly reduced ATP binding (at 4°C) at the mutated NBD1 and the intact NBD2 and Vi dependent ADP trapping at 37°C, but never completely abolished ATP-dependent solute transport.
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ABCC1 p.Lys684Arg 17295059:256:104
status: NEW257 In addition, these mutations, such as K684R [61], did not affect LTC4 binding and ATPγS or ATP + Vi did not inhibit LTC4 labeling.
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ABCC1 p.Lys684Arg 17295059:257:38
status: NEW[hide] Molecular mechanism of ATP-dependent solute transp... Methods Mol Biol. 2010;596:223-49. Chang XB
Molecular mechanism of ATP-dependent solute transport by multidrug resistance-associated protein 1.
Methods Mol Biol. 2010;596:223-49., [PMID:19949927]
Abstract [show]
Millions of new cancer patients are diagnosed each year and over half of these patients die from this devastating disease. Thus, cancer causes a major public health problem worldwide. Chemotherapy remains the principal mode to treat many metastatic cancers. However, occurrence of cellular multidrug resistance (MDR) prevents efficient killing of cancer cells, leading to chemotherapeutic treatment failure. Over-expression of ATP-binding cassette transporters, such as P-glycoprotein, breast cancer resistance protein and/or multidrug resistance-associated protein 1 (MRP1), confers an acquired MDR due to their capabilities of transporting a broad range of chemically diverse anticancer drugs across the cell membrane barrier. In this review, the molecular mechanism of ATP-dependent solute transport by MRP1 will be addressed.
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No. Sentence Comment
157 Indeed, several mutations, such as K684E, K1333E, K684R, K1333R, D792N, D1454N, G771A and G1433A, significantly diminished ATP binding and lost the ability to shift the bound substrate from high to low affinity site (99).
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ABCC1 p.Lys684Arg 19949927:157:50
status: NEW