title: Distinct conformational spectrum of homologous multidrug ABC transporters.
abstract: ATP-binding cassette (ABC) exporters are ubiquitously found in all kingdoms of life and their members play significant roles in mediating drug pharmacokinetics and multidrug resistance in the clinic. Significant questions and controversies remain regarding the relevance of their conformations observed in X-ray structures, their structural dynamics, and mechanism of transport. Here, we used single particle electron microscopy (EM) to delineate the entire conformational spectrum of two homologous ABC exporters (bacterial MsbA and mammalian P-glycoprotein) and the influence of nucleotide and substrate binding. Newly developed amphiphiles in complex with lipids that support high protein stability and activity enabled EM visualization of individual complexes in a membrane-mimicking environment. The data provide a comprehensive view of the conformational flexibility of these ABC exporters under various states and demonstrate not only similarities but striking differences between their mechanistic and energetic regulation of conformational changes.
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; The National Resource for Automated Molecular Microscopy, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Arne
authors: A
authors: Moeller
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Sung Chang
authors: SC
authors: Lee
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Houchao
authors: H
authors: Tao
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; The National Resource for Automated Molecular Microscopy, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Jeffrey A
authors: JA
authors: Speir
authors: Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors: Geoffrey
authors: G
authors: Chang
authors: Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
authors: Ina L
authors: IL
authors: Urbatsch
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; The National Resource for Automated Molecular Microscopy, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Clinton S
authors: CS
authors: Potter
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; The National Resource for Automated Molecular Microscopy, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: bcarr@nysbc.org.
authors: Bridget
authors: B
authors: Carragher
authors: Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: qinghai@scripps.edu.
authors: Qinghai
authors: Q
authors: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry*; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000648:ultrastructure*; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000648:ultrastructure*; D008563:Membrane Lipids / Q000737:chemistry; D051379:Mice; D008854:Microscopy, Electron; D008958:Models, Molecular; D009711:Nucleotides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D040681:Structural Homology, Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D008563:Membrane Lipids; C079726:MsbA protein, Bacteria; D009711:Nucleotides