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- PDB-7svd: The complex of phosphorylated human cystic fibrosis transmembrane... -
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Basic information
Entry | Database: PDB / ID: 7svd | |||||||||
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Title | The complex of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Lumacaftor (VX-809) | |||||||||
![]() | (Cystic fibrosis transmembrane conductance ...) x 2 | |||||||||
![]() | ATP-BINDING PROTEIN / ABC transporter / ion channel / folding correction / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() 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 / intracellular pH elevation / amelogenesis ...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 / intracellular pH elevation / amelogenesis / chloride channel inhibitor activity / ATPase-coupled inorganic anion transmembrane transporter activity / Golgi-associated vesicle membrane / multicellular organismal-level water homeostasis / cholesterol transport / membrane hyperpolarization / bicarbonate transport / bicarbonate transmembrane transporter activity / vesicle docking involved in exocytosis / chloride channel regulator activity / chloride transmembrane transporter activity / sperm capacitation / chloride channel activity / cholesterol biosynthetic process / RHOQ GTPase cycle / positive regulation of exocytosis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / chloride channel complex / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / cellular response to cAMP / cellular response to forskolin / chloride transmembrane transport / response to endoplasmic reticulum stress / isomerase activity / establishment of localization in cell / PDZ domain binding / Defective CFTR causes cystic fibrosis / Late endosomal microautophagy / clathrin-coated endocytic vesicle membrane / 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 | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||
![]() | Fiedorczuk, K. / Chen, J. | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Mechanism of CFTR correction by type I folding correctors. Authors: Karol Fiedorczuk / Jue Chen / ![]() Abstract: Small molecule chaperones have been exploited as therapeutics for the hundreds of diseases caused by protein misfolding. The most successful examples are the CFTR correctors, which transformed cystic ...Small molecule chaperones have been exploited as therapeutics for the hundreds of diseases caused by protein misfolding. The most successful examples are the CFTR correctors, which transformed cystic fibrosis therapy. These molecules revert folding defects of the ΔF508 mutant and are widely used to treat patients. To investigate the molecular mechanism of their action, we determined cryo-electron microscopy structures of CFTR in complex with the FDA-approved correctors lumacaftor or tezacaftor. Both drugs insert into a hydrophobic pocket in the first transmembrane domain (TMD1), linking together four helices that are thermodynamically unstable. Mutating residues at the binding site rendered ΔF508-CFTR insensitive to lumacaftor and tezacaftor, underscoring the functional significance of the structural discovery. These results support a mechanism in which the correctors stabilize TMD1 at an early stage of biogenesis, prevent its premature degradation, and thereby allosterically rescuing many disease-causing mutations. | |||||||||
History |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 232.4 KB | Display | ![]() |
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PDB format | ![]() | 178.6 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 25447MC ![]() 7sv7C ![]() 7svrC C: citing same article ( M: map data used to model this data |
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Similar structure data | |
EM raw data | ![]() Data size: 5.8 TB Data #1: Unaligned multi-frame micrographs of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Lumacaftor (VX-809) [micrographs - multiframe]) |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Cystic fibrosis transmembrane conductance ... , 2 types, 2 molecules AB
#1: Protein | Mass: 168334.469 Da / Num. of mol.: 1 / Mutation: E1371Q Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P13569, channel-conductance-controlling ATPase |
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#2: Protein/peptide | Mass: 1464.797 Da / Num. of mol.: 1 / Fragment: unstructured R-domain of CFTR Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Non-polymers , 8 types, 14 molecules ![](data/chem/img/MG.gif)
![](data/chem/img/ATP.gif)
![](data/chem/img/D12.gif)
![](data/chem/img/D10.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/VX8.gif)
![](data/chem/img/UNX.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/ATP.gif)
![](data/chem/img/D12.gif)
![](data/chem/img/D10.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/VX8.gif)
![](data/chem/img/UNX.gif)
![](data/chem/img/HOH.gif)
#3: Chemical | #4: Chemical | #5: Chemical | ChemComp-D12 / | #6: Chemical | #7: Chemical | #8: Chemical | ChemComp-VX8 / | #9: Chemical | ChemComp-UNX / | #10: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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Sequence details | Chain B is R-domain of the CFTR polypeptide chain and is mostly unstructured. It is not possible to ...Chain B is R-domain of the CFTR polypeptide chain and is mostly unstructured. It is not possible to assign it a sequence or correct registry. |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: The complex of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Lumacaftor (VX-809) Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 98 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
Software | Name: PHENIX / Version: 1.18.2_3874: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 52920 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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