title: Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein.
abstract: P-glycoprotein (P-gp) is a transporter of great clinical and pharmacological significance. Several structural studies of P-gp and its homologs have provided insights into its transport cycle, but questions remain regarding how P-gp recognizes diverse substrates and how substrate binding is coupled to ATP hydrolysis. Here, four new P-gp co-crystal structures with a series of rationally designed ligands are presented. It is observed that the binding of certain ligands, including an ATP-hydrolysis stimulator, produces a large conformational change in the fourth transmembrane helix, which is positioned to potentially transmit a signal to the nucleotide-binding domains. A new ligand-binding site on the surface of P-gp facing the inner leaflet of the membrane is also described, providing vital insights regarding the entry mechanism of hydrophobic drugs and lipids into P-gp. These results represent significant advances in the understanding of how P-gp and related transporters bind and export a plethora of metabolites, antibiotics and clinically approved and pipeline drugs.
authors.affiliation: Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92023, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Szewczyk
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Houchao
authors.initials: H
authors.lastname: Tao
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: McGrath
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Villaluz
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of California, La Jolla, CA 92023, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rees
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Sung Chang
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Rupak
authors.initials: R
authors.lastname: Doshi
authors.affiliation: Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
authors.forename: Ina L
authors.initials: IL
authors.lastname: Urbatsch
authors.affiliation: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Chang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000255:Adenosine Triphosphate
keywords: P-glycoprotein