ABCB1 p.Met986Arg
| Predicted by SNAP2: | A: D (71%), C: D (66%), D: D (85%), E: D (80%), F: N (57%), G: D (75%), H: D (85%), I: N (57%), K: D (91%), L: N (53%), N: D (80%), P: D (91%), Q: N (53%), R: D (80%), S: D (75%), T: N (57%), V: N (53%), W: D (66%), Y: D (71%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D, |
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[hide] Catalytic transitions in the human MDR1 P-glycopro... Biochemistry. 2012 Jun 26;51(25):5125-41. Epub 2012 Jun 12. Wise JG
Catalytic transitions in the human MDR1 P-glycoprotein drug binding sites.
Biochemistry. 2012 Jun 26;51(25):5125-41. Epub 2012 Jun 12., [PMID:22647192]
Abstract [show]
Multidrug resistance proteins that belong to the ATP-binding cassette family like the human P-glycoprotein (ABCB1 or Pgp) are responsible for many failed cancer and antiviral chemotherapies because these membrane transporters remove the chemotherapeutics from the targeted cells. Understanding the details of the catalytic mechanism of Pgp is therefore critical to the development of inhibitors that might overcome these resistances. In this work, targeted molecular dynamics techniques were used to elucidate catalytically relevant structures of Pgp. Crystal structures of homologues in four different conformations were used as intermediate targets in the dynamics simulations. Transitions from conformations that were wide open to the cytoplasm to transition state conformations that were wide open to the extracellular space were studied. Twenty-six nonredundant transitional protein structures were identified from these targeted molecular dynamics simulations using evolutionary structure analyses. Coupled movement of nucleotide binding domains (NBDs) and transmembrane domains (TMDs) that form the drug binding cavities were observed. Pronounced twisting of the NBDs as they approached each other as well as the quantification of a dramatic opening of the TMDs to the extracellular space as the ATP hydrolysis transition state was reached were observed. Docking interactions of 21 known transport ligands or inhibitors were analyzed with each of the 26 transitional structures. Many of the docking results obtained here were validated by previously published biochemical determinations. As the ATP hydrolysis transition state was approached, drug docking in the extracellular half of the transmembrane domains seemed to be destabilized as transport ligand exit gates opened to the extracellular space.
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No. Sentence Comment
333 A novel arginine mutagenesis approach for rescuing Pgp folding mutants was used by Loo and Clarke to argue that the bulky arginine side chain, when present in the drug binding site, mimicked the rescue of folding of certain mutations by transport substrates that has been observed.81 Alteration of known substrate affinities was taken as evidence that the A302R, F336R, L339R, G872R, F942R, Q946R, V982R, S993R, and M986R mutations were at drug binding locations.
X
ABCB1 p.Met986Arg 22647192:333:416
status: NEW