Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors.
ATP Binding Cassette Transporter, Subfamily B
/ antagonists & inhibitors
Adenosine Triphosphate
/ chemistry
Allosteric Regulation
Biological Transport
Dibenzocycloheptenes
/ chemistry
Electron Spin Resonance Spectroscopy
Humans
Hydrolysis
Models, Chemical
Protein Structure, Secondary
Quinolines
/ chemistry
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
17 05 2019
17 05 2019
Historique:
received:
02
11
2018
accepted:
17
04
2019
entrez:
18
5
2019
pubmed:
18
5
2019
medline:
18
12
2019
Statut:
ppublish
Résumé
The ATP-binding cassette subfamily B member 1 (ABCB1) multidrug transporter P-glycoprotein plays a central role in clearance of xenobiotics in humans and is implicated in cancer resistance to chemotherapy. We used double electron electron resonance spectroscopy to uncover the basis of stimulation of P-glycoprotein adenosine 5'-triphosphate (ATP) hydrolysis by multiple substrates and illuminate how substrates and inhibitors differentially affect its transport function. Our results reveal that substrate-induced acceleration of ATP hydrolysis correlates with stabilization of a high-energy, post-ATP hydrolysis state characterized by structurally asymmetric nucleotide-binding sites. By contrast, this state is destabilized in the substrate-free cycle and by high-affinity inhibitors in favor of structurally symmetric nucleotide binding sites. Together with previous data, our findings lead to a general model of substrate and inhibitor coupling to P-glycoprotein.
Identifiants
pubmed: 31097669
pii: 364/6441/689
doi: 10.1126/science.aav9406
pmc: PMC6890515
mid: NIHMS1060216
doi:
Substances chimiques
ABCB1 protein, human
0
ATP Binding Cassette Transporter, Subfamily B
0
Dibenzocycloheptenes
0
Quinolines
0
zosuquidar trihydrochloride
813AGY3126
Adenosine Triphosphate
8L70Q75FXE
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
689-692Subventions
Organisme : NIGMS NIH HHS
ID : U54 GM087519
Pays : United States
Informations de copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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