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	Tracing the substrate translocation mechanism in P-glycoprotein.
Journal, issue, pages	Elife, Vol. 12, Year 2024
Publish date	Jan 23, 2024
Authors	Theresa Gewering / Deepali Waghray / Kristian Parey / Hendrik Jung / Nghi N B Tran / Joel Zapata / Pengyi Zhao / Hao Chen / Dovile Januliene / Gerhard Hummer / Ina Urbatsch / Arne Moeller / Qinghai Zhang /
PubMed Abstract	P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and mediates the bioavailability ...P-glycoprotein (Pgp) is a prototypical ATP-binding cassette (ABC) transporter of great biological and clinical significance.Pgp confers cancer multidrug resistance and mediates the bioavailability and pharmacokinetics of many drugs (Juliano and Ling, 1976; Ueda et al., 1986; Sharom, 2011). Decades of structural and biochemical studies have provided insights into how Pgp binds diverse compounds (Loo and Clarke, 2000; Loo et al., 2009; Aller et al., 2009; Alam et al., 2019; Nosol et al., 2020; Chufan et al., 2015), but how they are translocated through the membrane has remained elusive. Here, we covalently attached a cyclic substrate to discrete sites of Pgp and determined multiple complex structures in inward- and outward-facing states by cryoEM. In conjunction with molecular dynamics simulations, our structures trace the substrate passage across the membrane and identify conformational changes in transmembrane helix 1 (TM1) as regulators of substrate transport. In mid-transport conformations, TM1 breaks at glycine 72. Mutation of this residue significantly impairs drug transport of Pgp in vivo, corroborating the importance of its regulatory role. Importantly, our data suggest that the cyclic substrate can exit Pgp without the requirement of a wide-open outward-facing conformation, diverting from the common efflux model for Pgp and other ABC exporters. The substrate transport mechanism of Pgp revealed here pinpoints critical targets for future drug discovery studies of this medically relevant system.
External links	Elife / PubMed:38259172 / PubMed Central
Methods	EM (single particle)
Resolution	2.6 - 4.7 Å
Structure data	14754 7zk4 EMDB-14754, PDB-7zk4: The ABCB1 L335C mutant (mABCB1) in the outward facing state Method: EM (single particle) / Resolution: 2.6 Å 14755 7zk5 EMDB-14755, PDB-7zk5: ABCB1 L335C mutant (mABCB1) in the outward facing state bound to AAC Method: EM (single particle) / Resolution: 2.6 Å 14756 7zk6 EMDB-14756, PDB-7zk6: ABCB1 L335C mutant (mABCB1) in the outward facing state bound to 2 molecules of AAC Method: EM (single particle) / Resolution: 3.1 Å 14758 7zk8 EMDB-14758, PDB-7zk8: ABCB1 L971C mutant (mABCB1) in the outward facing state bound to AAC Method: EM (single particle) / Resolution: 3.0 Å 14759 7zk9 EMDB-14759, PDB-7zk9: ABCB1 L971C mutant (mABCB1) in the inward facing state Method: EM (single particle) / Resolution: 4.3 Å 14760 7zka EMDB-14760, PDB-7zka: ABCB1 V978C mutant (mABCB1) in the outward facing state bound to AAC Method: EM (single particle) / Resolution: 2.9 Å 14761 7zkb EMDB-14761, PDB-7zkb: ABCB1 V978C mutant (mABCB1) in the inward facing state Method: EM (single particle) / Resolution: 4.7 Å 15687 8avy EMDB-15687, PDB-8avy: The ABCB1 L335C mutant (mABCB1) in the Apo state Method: EM (single particle) / Resolution: 2.9 Å 17630 8pee EMDB-17630, PDB-8pee: ABCB1 L335C mutant (mABCB1) in the inward facing state bound to AAC Method: EM (single particle) / Resolution: 3.8 Å
Chemicals	ChemComp-ATP: ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying moleculeYM / Adenosine triphosphate ChemComp-MG: Unknown entry ChemComp-Y01: CHOLESTEROL HEMISUCCINATE ChemComp-HOH: WATER / Water ChemComp-JIZ: (4~{S},11~{S},18~{S})-4,11-dimethyl-18-(sulfanylmethyl)-6,13,20-trithia-3,10,17,22,23,24-hexazatetracyclo[17.2.1.1^{5,8}.1^{12,15}]tetracosa-1(21),5(24),7,12(23),14,19(22)-hexaene-2,9,16-trione ChemComp-JJI: (4S,11S,18S)-4-[[(2,4-dinitrophenyl)disulfanyl]methyl]-11,18-dimethyl-6,13,20-trithia-3,10,17,22,23,24-hexazatetracyclo[17.2.1.1^{5,8}.1^{12,15}]tetracosa-1(21),5(24),7,12(23),14,19(22)-hexaene-2,9,16-trione ChemComp-LMN: Lauryl Maltose Neopentyl Glycol / detergentYM
Source	mus musculus (house mouse)
Keywords	MEMBRANE PROTEIN / ABC transporter