|Entry||Database: PDB / ID: 6fn1|
|Title||Zosuquidar and UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM)|
|Keywords||MEMBRANE PROTEIN / Membrane Transport Protein ABCB1 ABC Exporter Small molecule inhibitor Antibody complex|
|Function / homology||Type I protein exporter / ABC transporter-like / ABC-family proteins mediated transport / Abacavir transmembrane transport / ABC transporter integral membrane type-1 fused domain profile. / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporters family signature. / ABC transporter transmembrane region / ABC transporter / ABC transporter type 1, transmembrane domain superfamily ...Type I protein exporter / ABC transporter-like / ABC-family proteins mediated transport / Abacavir transmembrane transport / ABC transporter integral membrane type-1 fused domain profile. / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporters family signature. / ABC transporter transmembrane region / ABC transporter / ABC transporter type 1, transmembrane domain superfamily / Multidrug resistance protein 1 / P-loop containing nucleoside triphosphate hydrolase / ABC transporter, conserved site / ABC transporter type 1, transmembrane domain / AAA+ ATPase domain / ceramide translocation / ceramide-translocating ATPase activity / positive regulation of anion channel activity / phosphatidylethanolamine-translocating ATPase activity / ABC-type xenobiotic transporter / phosphatidylcholine-translocating ATPase activity / regulation of response to osmotic stress / phospholipid translocation / xenobiotic transmembrane transporting ATPase activity / stem cell proliferation / ATPase activity, coupled to transmembrane movement of substances / transporter activity / regulation of chloride transport / transmembrane transport / apical plasma membrane / G2/M transition of mitotic cell cycle / response to drug / cell surface / extracellular exosome / membrane / integral component of membrane / ATP binding / plasma membrane / Multidrug resistance protein 1|
Function and homology information
|Specimen source||Homo sapiens (human)|
Mus musculus (house mouse)
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 3.58 Å resolution|
|Authors||Alam, A. / Locher, K.P.|
|Citation||Journal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2018|
Title: Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1.
Authors: Amer Alam / Raphael Küng / Julia Kowal / Robert A McLeod / Nina Tremp / Eugenia V Broude / Igor B Roninson / Henning Stahlberg / Kaspar P Locher
Abstract: The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer ...The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes.
SummaryFull reportAbout validation report
|Date||Deposition: Feb 2, 2018 / Release: Feb 21, 2018|
|Structure viewer||Molecule: |
Downloads & links
A: Human-mouse chimeric ABCB1 (ABCBHM)
B: UIC2 Antigen Binding Fragment Light chain
C: UIC2 Antigen Binding Fragment Heavy Chain
|#1: Protein/peptide|| |
Mass: 137719.953 Da / Num. of mol.: 1 / Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK / Production host: Homo sapiens (human) / References: UniProt: P08183*PLUS
|#2: Protein/peptide|| |
Mass: 24321.039 Da / Num. of mol.: 1 / Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): Hybridoma / Production host: Mus musculus (house mouse)
|#3: Protein/peptide|| |
Mass: 24381.281 Da / Num. of mol.: 1 / Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): Hybridoma / Production host: Mus musculus (house mouse)
|#4: Chemical||#5: Chemical|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / Reconstruction method: single particle reconstruction|
|Molecular weight||Value: 0.195 MDa / Experimental value: NO|
|Buffer solution||pH: 7.5|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Vitrification||Cryogen name: ETHANE|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Microscope model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy|
|Image recording||Electron dose: 1.54 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)|
|Software||Name: PHENIX / Version: 1.12_2829: / Classification: refinement|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Symmetry||Point symmetry: C1|
|3D reconstruction||Resolution: 3.58 / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 231969 / Symmetry type: POINT|
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