Understanding polyspecificity of multidrug ABC transporters: closing in on the gaps in ABCB1.
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.
Gutmann
Daniel A P
DA
Department of Pharmacology, University of Cambridge, Cambridge, UK.
Ward
Andrew
A
Urbatsch
Ina L
IL
Chang
Geoffrey
G
van Veen
Hendrik W
HW
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
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