ABCB4 p.Gly602Ala
| Predicted by SNAP2: | A: N (72%), C: N (57%), D: D (71%), E: D (75%), F: D (59%), H: D (71%), I: D (66%), K: D (80%), L: D (66%), M: D (66%), N: D (66%), P: D (80%), Q: D (71%), R: D (80%), S: N (72%), T: N (72%), V: N (57%), W: D (75%), Y: D (53%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: 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] Localization of putative binding sites for cyclic ... BMC Struct Biol. 2013 May 6;13:7. doi: 10.1186/1472-6807-13-7. Honorat M, Terreux R, Falson P, Di Pietro A, Dumontet C, Payen L
Localization of putative binding sites for cyclic guanosine monophosphate and the anti-cancer drug 5-fluoro-2'-deoxyuridine-5'-monophosphate on ABCC11 in silico models.
BMC Struct Biol. 2013 May 6;13:7. doi: 10.1186/1472-6807-13-7., [PMID:23641929]
Abstract [show]
BACKGROUND: The Multidrug Resistance Protein ABCC11/MRP8 is expressed in physiological barriers and tumor breast tissues in which it secretes various substrates including cGMP (cyclic guanosine monophosphate) and 5FdUMP (5-fluoro-2'-deoxyuridine-5'-monophosphate), the active metabolite of the anticancer drug 5-FluoroUracil (frequently included to anticancer therapy).Previously, we described that ABCC11 high levels are associated to the estrogen receptor (ER) expression level in breast tumors and in cell lines resistant to tamoxifen. Consequently, by lowering the intracellular concentration of anticancer drugs, ABCC11 likely promotes a multidrug resistance (MDR) phenotype and decreases efficiency of anticancer therapy of 5FdUMP. Since no experimental data about binding sites of ABCC11 substrate are available, we decided to in silico localize putative substrate interaction sites of the nucleotide derivatives. Taking advantage of molecular dynamics simulation, we also analysed their evolution under computational physiological conditions and during the time. RESULTS: Since ABCC11 crystal structure is not resolved yet, we used the X-ray structures of the mouse mdr3 (homologous to human ABCB1) and of the bacterial homolog Sav1866 to generate two independent ABCC11 homology models in inward- and outward-facing conformations. Based on docking analyses, two putative binding pockets, for cGMP and 5FdUMP, were localized in both inward- and outward-facing conformations. Furthermore, based on our 3D models, and available biochemical data from homologous transporters, we identified several residues, potentially critical in ABCC11 transport function. Additionally, molecular dynamics simulation on our inward-facing model revealed for the first time conformation changes assumed to occur during transport process. CONCLUSIONS: ABCC11 would present two binding sites for cGMP and for 5FdUMP. Substrates likely first bind at the intracellular side of the transmembrane segment while ABCC11 is open forward the cytoplasm (inward-facing conformation). Then, along with conformational changes, it would pass through ABCC11 and fix the second site (close to the extracellular side), until the protein open itself to the extracellular space and allow substrate release.
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No. Sentence Comment
100 Insight in the impact of Glycine 180 polymorphism Gly180, found to be inside pocket 2, is prone to G602A SNP (single nucleotide polymorphism) inducing the Gly180Arg mutation which was correlated to earwax type [31], and to colostrum and sweat secretion defaults [32,33].
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ABCB4 p.Gly602Ala 23641929:100:99
status: NEW