8sa0

CryoEM structure of P-Glycoprotein in occluded closed state under continuous turnover conditions with verapamil

spinqualitylabelsall models 8sa0, resolution 4.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8sa0 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 4.1Å Ligands: ATP, I6H, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease MDR1_HUMAN Ulcerative colitis. Disease susceptibility is associated with variations affecting the gene represented in this entry. Function MDR1_HUMAN Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. Publication Abstract from PubMed P-glycoprotein (Pgp) is an important human multidrug transporter that contributes to pharmacokinetics and multidrug resistance. Despite decades of study, the conformation transition cycle of Pgp undergoing active drug transport is not defined, thus the precise relevance of all available Pgp structures to uninterrupted multidrug transport remains unclear. Here, we use cryo-EM of membrane-embedded human Pgp under continuous turnover conditions to analyze the conformational ensembles of Pgp transporting distinct substrates. These results delineate multiple conformations including inward-facing and closed conformations, highlighting the occluded conformation as a critical intermediate state between transporter closure and substrate release. A combination of structural, functional, and computational studies reveals the transmembrane helices 4 and 10 undergoing drastic rearrangement to coordinate substrate binding, occlusion, and release, and identifies a peripheral site involved in substrate capture and Pgp inhibition. Together, our results provide a set of snapshots of Pgp undergoing continuous drug transport, unveiling the intricate interplay between transporter dynamics and drug movement, and shed light on the mechanism of polyspecificity. , PMID:40240353 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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