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

Article

关键词: NUCLEOTIDE-BINDING DOMAINS;    GUI MEMBRANE-BUILDER;    ATP HYDROLYSIS;    CATALYTIC CYCLE;    DISTANCE MEASUREMENTS;    GLUTAMATE RESIDUES;    MOLECULAR-DYNAMICS;    FORCE-FIELD;    CHARMM;    CONFORMATION;   

DOI  :  10.1038/nature21414

来源: SCIE

【 摘 要 】

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)(1-4). 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 resonance(5,6) 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 chemotherapy(7). 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.

【 授权许可】

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