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Science ; 364(6441): 689-692, 2019 05 17.
Article in English | MEDLINE | ID: mdl-31097669

ABSTRACT

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.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/chemistry , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Allosteric Regulation , Biological Transport , Dibenzocycloheptenes/chemistry , Dibenzocycloheptenes/pharmacology , Electron Spin Resonance Spectroscopy , Humans , Hydrolysis , Models, Chemical , Protein Structure, Secondary , Quinolines/chemistry , Quinolines/pharmacology
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