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Yorodumi- PDB-6fn4: Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM) -
+Open data
-Basic information
Entry | Database: PDB / ID: 6fn4 | ||||||||||||
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Title | Apo form of UIC2 Fab complex of human-mouse chimeric ABCB1 (ABCB1HM) | ||||||||||||
Components |
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Keywords | MEMBRANE PROTEIN / Membrane Transport Protein ABCB1 ABC Exporter Small molecule inhibitor Antibody complex | ||||||||||||
Function / homology | Function and homology information positive regulation of anion channel activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / regulation of response to osmotic stress / floppase activity / Abacavir transmembrane transport / ceramide translocation / external side of apical plasma membrane ...positive regulation of anion channel activity / carboxylic acid transmembrane transport / carboxylic acid transmembrane transporter activity / terpenoid transport / ceramide floppase activity / regulation of response to osmotic stress / floppase activity / Abacavir transmembrane transport / ceramide translocation / external side of apical plasma membrane / Atorvastatin ADME / phosphatidylethanolamine flippase activity / xenobiotic transport across blood-brain barrier / phosphatidylcholine floppase activity / transepithelial transport / xenobiotic detoxification by transmembrane export across the plasma membrane / export across plasma membrane / ABC-type xenobiotic transporter / P-type phospholipid transporter / ABC-type xenobiotic transporter activity / phospholipid translocation / Prednisone ADME / efflux transmembrane transporter activity / xenobiotic transmembrane transporter activity / transmembrane transporter activity / transport across blood-brain barrier / ATPase-coupled transmembrane transporter activity / xenobiotic metabolic process / regulation of chloride transport / stem cell proliferation / ABC-family proteins mediated transport / transmembrane transport / G2/M transition of mitotic cell cycle / apical plasma membrane / response to xenobiotic stimulus / ubiquitin protein ligase binding / cell surface / ATP hydrolysis activity / extracellular exosome / ATP binding / membrane / plasma membrane / cytoplasm Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.14 Å | ||||||||||||
Authors | Alam, A. / Locher, K.P. | ||||||||||||
Funding support | Switzerland, United States, 3items
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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. | ||||||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 6fn4.cif.gz | 299.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6fn4.ent.gz | 246.7 KB | Display | PDB format |
PDBx/mmJSON format | 6fn4.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6fn4_validation.pdf.gz | 882.6 KB | Display | wwPDB validaton report |
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Full document | 6fn4_full_validation.pdf.gz | 905.1 KB | Display | |
Data in XML | 6fn4_validation.xml.gz | 48.7 KB | Display | |
Data in CIF | 6fn4_validation.cif.gz | 73 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/fn/6fn4 ftp://data.pdbj.org/pub/pdb/validation_reports/fn/6fn4 | HTTPS FTP |
-Related structure data
Related structure data | 4282MC 4281C 4283C 4284C 4285C 6fn1C C: citing same article (ref.) M: map data used to model this data |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 141283.156 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / References: UniProt: P08183*PLUS | ||||
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#2: Antibody | Mass: 24321.039 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse) | ||||
#3: Antibody | Mass: 24381.281 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse) | ||||
#4: Sugar | #5: Chemical | ChemComp-3PE / | Sequence details | Uniprot IDs: Human ABCB1 P08183. Mouse ABCB1 P21447 | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
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Molecular weight |
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Source (natural) |
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Source (recombinant) |
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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
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 0.9 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.12_2829: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||
3D reconstruction | Resolution: 4.14 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 517053 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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