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

P‐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‐electron...

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Bibliographic Details
Published in:FEBS letters 2021-03, Vol.595 (6), p.750-762
Main Authors: Lusvarghi, Sabrina, Durell, Stewart R., Ambudkar, Suresh V.
Format: Article
Language:English
Subjects:
ABC transporter
Adenosine Triphosphate - chemistry
Adenosine Triphosphate - metabolism
Amino Acid Substitution
ATP Binding Cassette Transporter, Subfamily B - chemistry
ATP Binding Cassette Transporter, Subfamily B - genetics
ATP Binding Cassette Transporter, Subfamily B - metabolism
ATP hydrolysis
Catalysis
catalytic cycle conformational changes
Humans
Hydrolysis
multidrug resistance
Mutation, Missense
Protein Binding
P‐glycoprotein
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Summary:P‐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‐electron 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 steps 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.
ISSN:0014-5793
1873-3468
DOI:10.1002/1873-3468.14054