Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Cryo-EM of human P-glycoprotein reveals an intermediate occluded conformation during active drug transport.
Journal, issue, pages	Nat Commun, Vol. 16, Issue 1, Page 3619, Year 2025
Publish date	Apr 16, 2025
Authors	Alan T Culbertson / Maofu Liao /
PubMed Abstract	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 ...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.
External links	Nat Commun / PubMed:40240353 / PubMed Central
Methods	EM (single particle)
Resolution	3.9 - 6.4 Å
Structure data	40226 8gmg EMDB-40226, PDB-8gmg: CryoEM structure of P-Glycoprotein in Apo state Method: EM (single particle) / Resolution: 4.3 Å 40227 8gmj EMDB-40227, PDB-8gmj: CryoEM structure of P-Glycoprotein in collapsed closed state under continuous turnover conditions with verapamil Method: EM (single particle) / Resolution: 4.4 Å 40258 8sa0 EMDB-40258, PDB-8sa0: CryoEM structure of P-Glycoprotein in occluded closed state under continuous turnover conditions with verapamil Method: EM (single particle) / Resolution: 4.1 Å 40259 8sa1 EMDB-40259, PDB-8sa1: CryoEM structure of P-Glycoprotein in inward facing 2 state under continuous turnover conditions with verapamil Method: EM (single particle) / Resolution: 4.4 Å 40292 8sb7 EMDB-40292, PDB-8sb7: CryoEM structure of P-Glycoprotein in inward facing 1 state under continuous turnover conditions with verapamil Method: EM (single particle) / Resolution: 4.0 Å 40293 8sb8 EMDB-40293, PDB-8sb8: CryoEM structure of P-Glycoprotein in collapsed closed state with vanadate Method: EM (single particle) / Resolution: 3.9 Å 40294 8sb9 EMDB-40294, PDB-8sb9: CryoEM structure of P-Glycoprotein in inward facing 1 state under continuous turnover conditions with vinblastine Method: EM (single particle) / Resolution: 4.1 Å 40295 8sba EMDB-40295, PDB-8sba: CryoEM structure of P-Glycoprotein in inward facing 2 state under continuous turnover conditions with vinblastine Method: EM (single particle) / Resolution: 3.9 Å EMDB-40326: CryoEM structure of P-Glycoprotein in inward facing state with MgATP and vanadate Method: EM (single particle) / Resolution: 4.5 Å EMDB-40340: CryoEM structure of P-Glycoprotein in inward facing state 1 with vinblastine Method: EM (single particle) / Resolution: 5.3 Å EMDB-40341: CryoEM structure of P-Glycoprotein in inward facing state 2 with vinblastine Method: EM (single particle) / Resolution: 4.5 Å EMDB-40342: CryoEM structure of P-Glycoprotein in closed 1 state under continuous turnover conditions with vinblastine Method: EM (single particle) / Resolution: 5.6 Å EMDB-40343: CryoEM structure of P-Glycoprotein in closed 2 state under continuous turnover conditions with vinblastine Method: EM (single particle) / Resolution: 6.4 Å
Chemicals	ChemComp-MG: Unknown entry ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying moleculeYM ChemComp-I6H: Dexverapamil / medication, channel blockerYM ChemComp-AOV: ADP ORTHOVANADATE / energy-carrying molecule analogueYM ChemComp-VLB: (2ALPHA,2'BETA,3BETA,4ALPHA,5BETA)-VINCALEUKOBLASTINE / medication, chemotherapyYM
Source	homo sapiens (human)
Keywords	TRANSPORT PROTEIN / multidrug resistance / ABC transporter / membrane protein / transporter / Transporter.