Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors

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Science  17 May 2019:
Vol. 364, Issue 6441, pp. 689-692
DOI: 10.1126/science.aav9406

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Transport control

The membrane protein P-glycoprotein protects cells by using energy from adenosine triphosphate (ATP) hydrolysis to expel chemical substances, including drugs. Inhibiting P-glycoprotein may thus ameliorate drug resistance. Structures of P-glycoprotein in the apo state and bound to substrate and inhibitor give insight into the transport mechanism, but a full picture requires access to substates in the transport cycle. Dastvan et al. used double electron electron resonance spectroscopy to show that substrates enhance transport by stabilizing an asymmetric post–ATP-hydrolysis state. By contrast, inhibitors stabilize a symmetric state that impairs transport.

Science, this issue p. 689


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.

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