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- EMDB-28161: The complex of phosphorylated human delta F508 cystic fibrosis tr... -
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Basic information
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Title | The complex of phosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) with Trikafta [elexacaftor (VX-445), tezacaftor (VX-661), ivacaftor (VX-770)] and ATP/Mg | |||||||||
![]() | del508CFTR phosphorylated in complex with Trikafta (tezacaftor, ivacaftor, elexacaftor) and ATP/Mg | |||||||||
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![]() | ABC transporter / ion channel / Trikafta / folding correction / membrane protein / ATP-Binding 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 | single particle reconstruction / cryo EM / Resolution: 3.0 Å | |||||||||
![]() | Fiedorczuk K / Chen J | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators. Authors: Karol Fiedorczuk / Jue Chen / ![]() Abstract: The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis ...The predominant mutation causing cystic fibrosis, a deletion of phenylalanine 508 (Δ508) in the cystic fibrosis transmembrane conductance regulator (CFTR), leads to severe defects in CFTR biogenesis and function. The advanced therapy Trikafta combines the folding corrector tezacaftor (VX-661), the channel potentiator ivacaftor (VX-770), and the dual-function modulator elexacaftor (VX-445). However, it is unclear how elexacaftor exerts its effects, in part because the structure of Δ508 CFTR is unknown. Here, we present cryo-electron microscopy structures of Δ508 CFTR in the absence and presence of CFTR modulators. When used alone, elexacaftor partially rectified interdomain assembly defects in Δ508 CFTR, but when combined with a type I corrector, did so fully. These data illustrate how the different modulators in Trikafta synergistically rescue Δ508 CFTR structure and function. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 304.5 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 19.5 KB 19.5 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 15.7 KB | Display | ![]() |
Images | ![]() | 100.7 KB | ||
Masks | ![]() | 325 MB | ![]() | |
Filedesc metadata | ![]() | 6.8 KB | ||
Others | ![]() ![]() | 260.2 MB 259.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8eiqMC ![]() 8eigC ![]() 8eioC ![]() 8ej1C M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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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 | del508CFTR phosphorylated in complex with Trikafta (tezacaftor, ivacaftor, elexacaftor) and ATP/Mg | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.676 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
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Projections & Slices |
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Density Histograms |
-Half map: Half map 1 of del508CFTR phosphorylated in complex...
File | emd_28161_half_map_1.map | ||||||||||||
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Annotation | Half map 1 of del508CFTR phosphorylated in complex with Trikafta (tezacaftor, lumacaftor, elexacaftor) and ATP/Mg | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map 2 of del508CFTR phosphorylated in complex...
File | emd_28161_half_map_2.map | ||||||||||||
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Annotation | Half map 2 of del508CFTR phosphorylated in complex with Trikafta (tezacaftor, lumacaftor, elexacaftor) and ATP/Mg | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
+Entire : The complex of phosphorylated human delta F508 cystic fibrosis tr...
+Supramolecule #1: The complex of phosphorylated human delta F508 cystic fibrosis tr...
+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: CHOLESTEROL
+Macromolecule #6: DODECANE
+Macromolecule #7: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-...
+Macromolecule #8: (6P)-N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluor...
+Macromolecule #9: Tezacaftor
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 5 mg/mL |
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Buffer | pH: 7.4 |
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 K3 (6k x 4k) / Average electron dose: 65.6 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |