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- EMDB-25445: The complex of phosphorylated human cystic fibrosis transmembrane... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-25445 | |||||||||
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Title | The complex of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Tezacaftor (VX-661) | |||||||||
![]() | E1371QCFTR/tezacaftor/ATP | |||||||||
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![]() | ABC transporter / ion channel / folding correction / ATP-BINDING PROTEIN / 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 / vesicle docking involved in exocytosis / bicarbonate transport / 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 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 | single particle reconstruction / cryo EM / Resolution: 3.8 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 | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 96.4 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 14.2 KB 14.2 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 10.7 KB | Display | ![]() |
Images | ![]() | 143 KB | ||
Filedesc metadata | ![]() | 6.5 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7sv7MC ![]() 7svdC ![]() 7svrC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | |
EM raw data | ![]() Data size: 1.8 TB Data #1: Unaligned multi-frame micrographs of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Tezacaftor (VX-661) [micrographs - multiframe]) |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | E1371QCFTR/tezacaftor/ATP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.03 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
+Entire : The complex of phosphorylated human cystic fibrosis transmembrane...
+Supramolecule #1: The complex of phosphorylated human cystic fibrosis transmembrane...
+Macromolecule #1: Cystic fibrosis transmembrane conductance regulator
+Macromolecule #2: Cystic fibrosis transmembrane conductance regulator
+Macromolecule #3: MAGNESIUM ION
+Macromolecule #4: ADENOSINE-5'-TRIPHOSPHATE
+Macromolecule #5: nonane
+Macromolecule #6: DODECANE
+Macromolecule #7: CHOLESTEROL
+Macromolecule #8: TETRADECANE
+Macromolecule #9: heptadecane
+Macromolecule #10: Tezacaftor
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 80.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |