ABCB1 p.Arg905Thr
| Predicted by SNAP2: | A: D (75%), C: D (75%), D: D (91%), E: D (85%), F: D (85%), G: D (85%), H: D (80%), I: D (80%), K: D (63%), L: D (85%), M: D (75%), N: D (80%), P: D (91%), Q: D (75%), S: D (71%), T: D (75%), V: D (85%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Translocation mechanism of P-glycoprotein and conf... Biochim Biophys Acta. 2014 Nov;1838(11):2882-98. doi: 10.1016/j.bbamem.2014.07.018. Epub 2014 Jul 25. Prajapati R, Sangamwar AT
Translocation mechanism of P-glycoprotein and conformational changes occurring at drug-binding site: Insights from multi-targeted molecular dynamics.
Biochim Biophys Acta. 2014 Nov;1838(11):2882-98. doi: 10.1016/j.bbamem.2014.07.018. Epub 2014 Jul 25., [PMID:25068895]
Abstract [show]
P-glycoprotein (P-gp) is well known for multidrug resistance in drug therapy. Its over-expression results into the increased efflux of therapeutic agents rendering them inefficacious. A clear understanding of P-gp efflux mechanism and substrate/inhibitor interactions during the course of efflux cycle will be crucial for designing effective P-gp inhibitors, and therapeutic agents that are non-substrate to P-gp. In the present work, we have modeled P-gp in three different catalytic states. These models were utilized for elucidation of P-gp translocation mechanism using multi-targeted molecular dynamics (MTMD). The gradual changes occurring in P-gp structure from inward open to outward open conformation were sampled out. A detailed investigation of conformational changes occurring in trans-membrane domains (TMDs) during the course of catalytic cycle was carried out. Movements of each TM helices in response to pronounced twisting and translatory motion of NBDs were measured quantitatively. The role of intracellular coupling helices (ICHs) during the structural transition of P-gp was studied, and observed as vital links for structural transition. A close observation of displacements and conformational changes in the residues lining drug-binding pocket was also carried out. Further, we have analyzed the molecular interactions of P-gp substrates/inhibitors during the P-gp translocation to find out how stable binding interactions of a compound at drug-binding site(s) in open conformation, becomes highly destabilized in closed conformation. The study revealed striking differences between the molecular interactions of substrate and inhibitor; inhibitors showed a tendency to maintain stable binding interactions during the catalytic transition cycle.
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No. Sentence Comment
260 (B) angular rotation between Cb1;-atoms of ICH4, ICH1 and NBD1 residues Arg 905-Thr 906-Val 907 (black), Asp 164-Val 165-His 166 (red) and Tyr 444-Asp 445-Pro 446 (green), respectively.
X
ABCB1 p.Arg905Thr 25068895:260:75
status: NEW