Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein

Author:  ["Brandy Verhalen","Reza Dastvan","Sundarapandian Thangapandian","Yelena Peskova","Hanane A. Koteiche","Robert K. Nakamoto","Emad Tajkhorshid","Hassane S. Mchaourab"]

Publication:  Nature

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Tags:     Mathematics

Abstract

Double electron–electron resonance and computer simulations are used to describe conformational dynamics in the ATP-binding cassette transporter Pgp, which has an important role in the clearance of xenobiotics and cancer resistance to chemotherapy. Despite numerous biochemical and structural studies, it remains unclear how ATP-binding cassette (ABC) transporters convert energy from ATP hydrolysis into the translocation of substrates across cellular membranes. Now, Hassane Mchaourab and colleagues have combined double electron–electron resonance (DEER) and computer simulations to describe a two-stroke ATP hydrolysis cycle that leads the mammalian ABC transporter Pgp from an inward- to an outward-facing conformation. The results have implications for basic cellular processes such as the clearance of xenobiotics as well as clinical issues such as cancer resistance to chemotherapy. ATP binding cassette (ABC) transporters of the exporter class harness the energy of ATP hydrolysis in the nucleotide-binding domains (NBDs) to power the energetically uphill efflux of substrates by a dedicated transmembrane domain (TMD)1,2,3,4. Although numerous investigations have described the mechanism of ATP hydrolysis and defined the architecture of ABC exporters, a detailed structural dynamic understanding of the transduction of ATP energy to the work of substrate translocation remains elusive. Here we used double electron–electron resonance5,6 and molecular dynamics simulations to describe the ATP- and substrate-coupled conformational cycle of the mouse ABC efflux transporter P-glycoprotein (Pgp; also known as ABCB1), which has a central role in the clearance of xenobiotics and in cancer resistance to chemotherapy7. Pairs of spin labels were introduced at residues selected to track the putative inward-facing to outward-facing transition. Our findings illuminate how ATP energy is harnessed in the NBDs in a two-stroke cycle and elucidate the consequent conformational motion that reconfigures the TMD, two critical aspects of Pgp transport mechanism. Along with a fully atomistic model of the outward-facing conformation in membranes, the insight into Pgp conformational dynamics harmonizes mechanistic and structural data into a novel perspective on ATP-coupled transport and reveals mechanistic divergence within the efflux class of ABC transporters.

Cite this article

Verhalen, B., Dastvan, R., Thangapandian, S. et al. Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein. Nature 543, 738–741 (2017). https://doi.org/10.1038/nature21414

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