Does the ATP ‐bound EQ mutant reflect the pre‐ or post‐ATP hydrolysis state in the catalytic cycle of human P‐glycoprotein (ABCB1)?

AbstractP ‐glycoprotein (P‐gp, ABCB1) is an ABC transporter associated with the development of multidrug resistance to chemotherapy. During its catalytic cycle, P‐gp undergoes significant conformational changes. Recently, atomic structures of some of these conformations have been resolved using cryo‐e lectron microscopy. The ATP hydrolysis‐defective mutant of the catalytic glutamate residue of the Walker B motif (E556Q/E1201Q) has been used to determine the structure of the ATP‐bound inward‐closed conformation of P‐gp. Here we show that this mutant does not appear to undergo the same step s as wild‐type P‐gp. We discuss conformational differences in the EQ mutant that may lead to a better understanding of the catalytic cycle of P‐gp and propose that additional structural studies with wild‐type P‐gp are required.

Source: FEBS Letters - February 6, 2021 Category: Biochemistry Authors: Sabrina Lusvarghi, Stewart R. Durell, Suresh V. Ambudkar Tags: RESEARCH LETTER Source Type: research