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Yorodumi- PDB-7a6f: Nanodisc reconstituted human ABCB1 in complex with MRK16 Fab and ... -
+Open data
-Basic information
Entry | Database: PDB / ID: 7a6f | ||||||
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Title | Nanodisc reconstituted human ABCB1 in complex with MRK16 Fab and zosuquidar | ||||||
Components |
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Keywords | TRANSPORT PROTEIN / P-glycoprotein / MDR1 / nanodisc | ||||||
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: 3.5 Å | ||||||
Authors | Nosol, K. / Locher, K.P. | ||||||
Funding support | Switzerland, 1items
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Citation | Journal: Proc Natl Acad Sci U S A / Year: 2020 Title: Cryo-EM structures reveal distinct mechanisms of inhibition of the human multidrug transporter ABCB1. Authors: Kamil Nosol / Ksenija Romane / Rossitza N Irobalieva / Amer Alam / Julia Kowal / Naoya Fujita / Kaspar P Locher / Abstract: ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and ...ABCB1 detoxifies cells by exporting diverse xenobiotic compounds, thereby limiting drug disposition and contributing to multidrug resistance in cancer cells. Multiple small-molecule inhibitors and inhibitory antibodies have been developed for therapeutic applications, but the structural basis of their activity is insufficiently understood. We determined cryo-EM structures of nanodisc-reconstituted, human ABCB1 in complex with the Fab fragment of the inhibitory, monoclonal antibody MRK16 and bound to a substrate (the antitumor drug vincristine) or to the potent inhibitors elacridar, tariquidar, or zosuquidar. We found that inhibitors bound in pairs, with one molecule lodged in the central drug-binding pocket and a second extending into a phenylalanine-rich cavity that we termed the "access tunnel." This finding explains how inhibitors can act as substrates at low concentration, but interfere with the early steps of the peristaltic extrusion mechanism at higher concentration. Our structural data will also help the development of more potent and selective ABCB1 inhibitors. | ||||||
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 | 7a6f.cif.gz | 285.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7a6f.ent.gz | 236.6 KB | Display | PDB format |
PDBx/mmJSON format | 7a6f.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7a6f_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 7a6f_full_validation.pdf.gz | 1.5 MB | Display | |
Data in XML | 7a6f_validation.xml.gz | 69.5 KB | Display | |
Data in CIF | 7a6f_validation.cif.gz | 102.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/a6/7a6f ftp://data.pdbj.org/pub/pdb/validation_reports/a6/7a6f | HTTPS FTP |
-Related structure data
Related structure data | 11672MC 7a65C 7a69C 7a6cC 7a6eC 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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-Components
#1: Protein | Mass: 141628.781 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ABCB1, MDR1, PGY1 / Production host: Homo sapiens (human) References: UniProt: P08183, ABC-type xenobiotic transporter, P-type phospholipid transporter | ||||
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#2: Antibody | Mass: 24139.758 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human) | ||||
#3: Antibody | Mass: 23415.236 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human) | ||||
#4: Chemical | #5: Chemical | ChemComp-CLR / Has ligand of interest | Y | |
-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 | Value: 0.24 MDa / Experimental value: YES | ||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) |
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Buffer solution | pH: 7.4 | ||||||||||||||||||||||||
Specimen | Conc.: 0.4 mg/ml / 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 / Cs: 2.7 mm / C2 aperture diameter: 100 µm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 32 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.17.1_3660: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 166803 / Symmetry type: POINT | ||||||||||||||||||||||||
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