ABCC1 p.Phe728Cys
| Predicted by SNAP2: | A: D (66%), C: D (63%), D: D (91%), E: D (85%), G: D (80%), H: D (80%), I: D (71%), K: D (85%), L: D (59%), M: N (57%), N: D (85%), P: D (91%), Q: D (80%), R: D (85%), S: D (80%), T: D (80%), V: D (71%), W: D (75%), Y: N (57%), |
| 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] Exhaustive sampling of docking poses reveals bindi... PLoS Comput Biol. 2011 May;7(5):e1002036. Epub 2011 May 12. Klepsch F, Chiba P, Ecker GF
Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein.
PLoS Comput Biol. 2011 May;7(5):e1002036. Epub 2011 May 12., [PMID:21589945]
Abstract [show]
Overexpression of the xenotoxin transporter P-glycoprotein (P-gp) represents one major reason for the development of multidrug resistance (MDR), leading to the failure of antibiotic and cancer therapies. Inhibitors of P-gp have thus been advocated as promising candidates for overcoming the problem of MDR. However, due to lack of a high-resolution structure the concrete mode of interaction of both substrates and inhibitors is still not known. Therefore, structure-based design studies have to rely on protein homology models. In order to identify binding hypotheses for propafenone-type P-gp inhibitors, five different propafenone derivatives with known structure-activity relationship (SAR) pattern were docked into homology models of the apo and the nucleotide-bound conformation of the transporter. To circumvent the uncertainty of scoring functions, we exhaustively sampled the pose space and analyzed the poses by combining information retrieved from SAR studies with common scaffold clustering. The results suggest propafenone binding at the transmembrane helices 5, 6, 7 and 8 in both models, with the amino acid residue Y307 playing a crucial role. The identified binding site in the non-energized state is overlapping with, but not identical to, known binding areas of cyclic P-gp inhibitors and verapamil. These findings support the idea of several small binding sites forming one large binding cavity. Furthermore, the binding hypotheses for both catalytic states were analyzed and showed only small differences in their protein-ligand interaction fingerprints, which indicates only small movements of the ligand during the catalytic cycle.
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No. Sentence Comment
244 Loo et al. also demonstrated that binding of vinblastine, cyclosporin A and rhodamine B could prevent the formation of a cross-link between L339C and F728C, suggesting that the ligands are at least partially located between these two residues [52].
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ABCC1 p.Phe728Cys 21589945:244:150
status: NEW[hide] Mutational analysis of ABC proteins. Arch Biochem Biophys. 2008 Aug 1;476(1):51-64. Epub 2008 Mar 5. Loo TW, Clarke DM
Mutational analysis of ABC proteins.
Arch Biochem Biophys. 2008 Aug 1;476(1):51-64. Epub 2008 Mar 5., [PMID:18328253]
Abstract [show]
The 49 human members of the ATP-binding cassette (ABC) family of proteins are involved in a wide range of activities such as active transport of compounds across membranes, extraction of compounds out of membranes, functioning as ion channels, or regulators of channel activity. Mutations and/or overexpression of many of the proteins can have adverse effects on health. A goal in the study of ABC proteins is to understand their mechanisms of action. This review will focus on the mutational approaches that have been used to study the structure and mechanisms of some ABC proteins.
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373 Introduction of the I306R(TM5) mutation into mutant L339C/F728C reduced its apparent affinity for vinblastine more than 60-fold but had little effect on its apparent affinity for rhodamine.
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ABCC1 p.Phe728Cys 18328253:373:58
status: NEW