Structural definition of polyspecific compensatory ligand recognition by P-glycoprotein.

IUCrJ
Christina A LeStephen G Aller

Abstract

The multidrug transporter P-glycoprotein (Pgp)/ABCB1/MDR1 plays an important role in multidrug resistance (MDR) and detoxification owing to its ability to efflux an unusually large and chemically diverse set of substrates. Previous phenylalanine-to-alanine scanning mutagenesis of Pgp revealed that nearly all mutations retained full MDR function and still permitted substrate transport. This suggests that either the loss of any single aromatic side chain did not affect the ligand-binding modes or that highly adaptive and compensatory drug recognition is an intrinsic property including ligand-binding shifts that preserve function. To explore this hypothesis, the ATPase function and crystallographic localization of five single-site mutations in which the native aromatic residue directly interacted with the environmental pollutant BDE-100, as shown in previous crystal structures, were tested. Two mutants, Y303A and Y306A, showed strong BDE-100 occupancy at the original site (site 1), but also revealed a novel site 2 located on the opposing pseudo-symmetric half of the drug-binding pocket (DBP). Surprisingly, the F724A mutant structure had no detectable binding in site 1 but exhibited a novel site shifted 11 Å from site 1. ATPase stu...Continue Reading

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Citations

Nov 13, 2020·FEBS Letters·Thomas StocknerLutz Schmitt
Jan 12, 2021·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Luciana MoscaGianni Colotti
Feb 18, 2021·Physical Chemistry Chemical Physics : PCCP·Bo ZhangQi Wang
Jun 12, 2021·Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP·Sascha C T NicklischAmro Hamdoun
Jul 11, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·M GanesanN Rajendra Prasad

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Methods Mentioned

BETA
X-ray
Protein Assay

Software Mentioned

2000
Phenix
PyMOL
SoftMax Pro
HKL
CNS
MolProbity
refine
GraphPad Prism
elbow

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