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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
TitleThe complex of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Lumacaftor (VX-809)
Components(Cystic fibrosis transmembrane conductance ...) x 2
KeywordsATP-BINDING PROTEIN / ABC transporter / ion channel / folding correction / MEMBRANE PROTEIN
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 / intracellular pH elevation / ATPase-coupled inorganic anion transmembrane transporter activity ...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 / ATPase-coupled inorganic anion transmembrane transporter activity / amelogenesis / chloride channel inhibitor activity / Golgi-associated vesicle membrane / multicellular organismal-level water homeostasis / vesicle docking involved in exocytosis / cholesterol transport / membrane hyperpolarization / bicarbonate transmembrane transporter activity / bicarbonate transport / 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 forskolin / cellular response to cAMP / isomerase activity / chloride transmembrane transport / response to endoplasmic reticulum stress / PDZ domain binding / establishment of localization in cell / Defective CFTR causes cystic fibrosis / clathrin-coated endocytic vesicle membrane / Late endosomal microautophagy / ABC-family proteins mediated transport / transmembrane transport / recycling endosome / 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
: / CFTR regulator domain / Cystic fibrosis TM conductance regulator (CFTR), regulator domain / Cystic fibrosis transmembrane conductance regulator / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. ...: / CFTR regulator domain / Cystic fibrosis TM conductance regulator (CFTR), regulator domain / Cystic fibrosis transmembrane conductance regulator / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / CHOLESTEROL / DECANE / DODECANE / Lumacaftor / Cystic fibrosis transmembrane conductance regulator
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsFiedorczuk, K. / Chen, J.
Funding support United States, 2items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
Cystic Fibrosis Foundation United States
CitationJournal: Cell / Year: 2022
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
DepositionNov 18, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 19, 2022Group: Database references / Category: citation
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 28, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

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Assembly

Deposited unit
A: Cystic fibrosis transmembrane conductance regulator
B: Cystic fibrosis transmembrane conductance regulator
hetero molecules


Theoretical massNumber of molelcules
Total (without water)173,03314
Polymers169,7992
Non-polymers3,23312
Water362
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Cystic fibrosis transmembrane conductance ... , 2 types, 2 molecules AB

#1: Protein Cystic fibrosis transmembrane conductance regulator / / CFTR / ATP-binding cassette sub-family C member 7 / Channel conductance-controlling ATPase / cAMP- ...CFTR / ATP-binding cassette sub-family C member 7 / Channel conductance-controlling ATPase / cAMP-dependent chloride channel


Mass: 168334.469 Da / Num. of mol.: 1 / Mutation: E1371Q
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, channel-conductance-controlling ATPase
#2: Protein/peptide Cystic fibrosis transmembrane conductance regulator /


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.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Non-polymers , 8 types, 14 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE / Adenosine triphosphate


Mass: 507.181 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
#5: Chemical ChemComp-D12 / DODECANE / Dodecane


Mass: 170.335 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H26
#6: Chemical ChemComp-D10 / DECANE / Decane


Mass: 142.282 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H22
#7: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O
#8: Chemical ChemComp-VX8 / Lumacaftor / 3-(6-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-3-methylpyridin-2-yl)benzoic acid / VX-809 / Lumacaftor


Mass: 452.407 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H18F2N2O5 / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-UNX / UNKNOWN ATOM OR ION


Mass: 103.120 Da / Num. of mol.: 1 / Source method: obtained synthetically
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Sequence detailsChain 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.

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 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
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 98 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 52920 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0059839
ELECTRON MICROSCOPYf_angle_d0.72313333
ELECTRON MICROSCOPYf_dihedral_angle_d20.2923667
ELECTRON MICROSCOPYf_chiral_restr0.2421547
ELECTRON MICROSCOPYf_plane_restr0.0041644

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