title: Understanding polyspecificity of multidrug ABC transporters: closing in on the gaps in ABCB1.
abstract: Multidrug ABC transporters can transport a wide range of drugs from the cell. Ongoing studies of the prototype mammalian multidrug resistance ATP-binding cassette transporter P-glycoprotein (ABCB1) have revealed many intriguing functional and biochemical features. However, a gap remains in our knowledge regarding the molecular basis of its broad specificity for structurally unrelated ligands. Recently, the first crystal structures of ligand-free and ligand-bound ABCB1 showed ligand binding in a cavity between its two membrane domains, and earlier observations on polyspecificity can now be interpreted in a structural context. Comparison of the new ABCB1 crystal structures with structures of bacterial homologs suggests a critical role for an axial rotation of transmembrane helices for high-affinity binding and low-affinity release of ligands during transmembrane transport.
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Daniel A P
authors.initials: DA
authors.lastname: Gutmann
authors.forename: Andrew
authors.initials: A
authors.lastname: Ward
authors.forename: Ina L
authors.initials: IL
authors.lastname: Urbatsch
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Chang
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: van Veen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001419:Bacteria / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry; D018360:Crystallography, X-Ray; D006460:Hemolysin Proteins / Q000737:chemistry; D006801:Humans; D013379:Substrate Specificity
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D002352:Carrier Proteins; D006460:Hemolysin Proteins; C050837:Hlyb protein, Bacteria; C507084:Abcb1b protein, mouse