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Yorodumi- PDB-6o2p: Complex of ivacaftor with cystic fibrosis transmembrane conductan... -
+Open data
-Basic information
Entry | Database: PDB / ID: 6o2p | |||||||||
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Title | Complex of ivacaftor with cystic fibrosis transmembrane conductance regulator (CFTR) | |||||||||
Components |
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Keywords | HYDROLASE / ABC transporter / anion channel / cystic fibrosis / membrane protein / ivacaftor | |||||||||
Function / homology | Function and homology information positive regulation of voltage-gated chloride channel activity / positive regulation of cyclic nucleotide-gated ion channel activity / Sec61 translocon complex binding / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / positive regulation of enamel mineralization / transepithelial water transport / RHO GTPases regulate CFTR trafficking / ATPase-coupled inorganic anion transmembrane transporter activity / intracellular pH elevation ...positive regulation of voltage-gated chloride channel activity / positive regulation of cyclic nucleotide-gated ion channel activity / Sec61 translocon complex binding / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / positive regulation of enamel mineralization / transepithelial water transport / RHO GTPases regulate CFTR trafficking / ATPase-coupled inorganic anion transmembrane transporter activity / intracellular pH elevation / amelogenesis / chloride channel inhibitor activity / Golgi-associated vesicle membrane / multicellular organismal-level water homeostasis / cholesterol transport / membrane hyperpolarization / bicarbonate transport / vesicle docking involved in exocytosis / bicarbonate transmembrane transporter activity / chloride channel regulator activity / chloride transmembrane transporter activity / sperm capacitation / chloride channel activity / cholesterol biosynthetic process / RHOQ GTPase cycle / positive regulation of insulin secretion involved in cellular response to glucose stimulus / positive regulation of exocytosis / chloride channel complex / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / cellular response to forskolin / cellular response to cAMP / chloride transmembrane transport / response to endoplasmic reticulum stress / isomerase activity / establishment of localization in cell / PDZ domain binding / Defective CFTR causes cystic fibrosis / clathrin-coated endocytic vesicle membrane / Late endosomal microautophagy / ABC-family proteins mediated transport / recycling endosome / transmembrane transport / Aggrephagy / Chaperone Mediated Autophagy / recycling endosome membrane / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / protein-folding chaperone binding / early endosome membrane / early endosome / endosome membrane / Ub-specific processing proteases / apical plasma membrane / lysosomal membrane / endoplasmic reticulum membrane / enzyme binding / cell surface / ATP hydrolysis activity / protein-containing complex / ATP binding / membrane / nucleus / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
Authors | Liu, F. / Zhang, Z. / Chen, J. / Levit, A. / Shoichet, B. | |||||||||
Funding support | United States, 1items
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Citation | Journal: Science / Year: 2019 Title: Structural identification of a hotspot on CFTR for potentiation. Authors: Fangyu Liu / Zhe Zhang / Anat Levit / Jesper Levring / Kouki K Touhara / Brian K Shoichet / Jue Chen / Abstract: Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve ...Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve folding of CFTR and potentiators that recover the function of CFTR. Here, we report two cryo-electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)-approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds. | |||||||||
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 | 6o2p.cif.gz | 267.4 KB | Display | PDBx/mmCIF format |
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PDB format | pdb6o2p.ent.gz | 203.7 KB | Display | PDB format |
PDBx/mmJSON format | 6o2p.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 6o2p_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 6o2p_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 6o2p_validation.xml.gz | 36.6 KB | Display | |
Data in CIF | 6o2p_validation.cif.gz | 55.3 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/o2/6o2p ftp://data.pdbj.org/pub/pdb/validation_reports/o2/6o2p | HTTPS FTP |
-Related structure data
Related structure data | 0611MC 0606C 6o1vC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein / Protein/peptide , 2 types, 2 molecules AB
#1: Protein | Mass: 169352.594 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: CFTR, ABCC7 / Production host: Homo sapiens (human) / References: UniProt: P13569, EC: 3.6.3.49 |
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#2: Protein/peptide | Mass: 1464.797 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
-Non-polymers , 5 types, 12 molecules
#3: Chemical | #4: Chemical | #5: Chemical | ChemComp-POV / ( #6: Chemical | ChemComp-AJP / | #7: Chemical | ChemComp-VX7 / | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Complex of ivacaftor and cystic fibrosis transmembrane conductance regulator (CFTR) Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Molecular weight | Value: 0.168 MDa / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) / Cell: HEK293S GnTI- / Plasmid: BacMam |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 5.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: unspecified |
Vitrification | Instrument: FEI VITROBOT MARK I / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K |
-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: 1.48 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
EM software |
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CTF correction | Type: NONE | |||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 510483 | |||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | |||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 490750 / Symmetry type: POINT | |||||||||||||||||||||||||||
Atomic model building | B value: 150 / Protocol: AB INITIO MODEL / Space: RECIPROCAL | |||||||||||||||||||||||||||
Atomic model building | PDB-ID: 6MSM Accession code: 6MSM / Source name: PDB / Type: experimental model |