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- PDB-8ej1: Dephosphorylated human delta F508 cystic fibrosis transmembrane c... -

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Basic information

Entry
Database: PDB / ID: 8ej1
TitleDephosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR)
ComponentsCystic fibrosis transmembrane conductance regulator
KeywordsATP-BINDING PROTEIN / ABC transporter / ion channel / folding correction / MEMBRANE PROTEIN / ISOMERASE
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 / 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 / bicarbonate transport / bicarbonate transmembrane transporter activity / membrane hyperpolarization / vesicle docking involved in exocytosis / chloride channel regulator activity / chloride transmembrane transporter activity / sperm capacitation / cholesterol biosynthetic process / chloride channel activity / RHOQ GTPase cycle / positive regulation of exocytosis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / ATPase-coupled transmembrane transporter activity / chloride channel complex / ABC-type transporter activity / cellular response to cAMP / 14-3-3 protein binding / cellular response to forskolin / response to endoplasmic reticulum stress / chloride transmembrane transport / PDZ domain binding / isomerase activity / establishment of localization in cell / Defective CFTR causes cystic fibrosis / clathrin-coated endocytic vesicle membrane / Late endosomal microautophagy / recycling endosome / ABC-family proteins mediated transport / transmembrane transport / recycling endosome membrane / Chaperone Mediated Autophagy / Aggrephagy / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / protein-folding chaperone binding / early endosome membrane / early endosome / Ub-specific processing proteases / endosome membrane / apical plasma membrane / lysosomal membrane / endoplasmic reticulum membrane / enzyme binding / cell surface / protein-containing complex / ATP hydrolysis activity / ATP binding / nucleus / membrane / 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 ...: / 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
Cystic fibrosis transmembrane conductance regulator
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.9 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: Science / Year: 2022
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
DepositionSep 16, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 19, 2022Provider: repository / Type: Initial release
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Revision 1.0Oct 19, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
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Revision 1.0Oct 19, 2022Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.1Nov 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.3May 14, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 14, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cystic fibrosis transmembrane conductance regulator


Theoretical massNumber of molelcules
Total (without water)168,1871
Polymers168,1871
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#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: 168187.297 Da / Num. of mol.: 1 / Mutation: E1371Q
Source method: isolated from a genetically manipulated source
Details: Protein is a human CFTR with F508 deletion and E1371Q substitution
Source: (gene. exp.) Homo sapiens (human) / Gene: CFTR, ABCC7 / Variant: delta F508 / Production host: Homo sapiens (human)
References: UniProt: P13569, channel-conductance-controlling ATPase
Has protein modificationN

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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: Dephosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR)
Type: COMPLEX / Entity ID: all / 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 FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 65.6 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 6.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 35461 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0015695
ELECTRON MICROSCOPYf_angle_d0.2757917
ELECTRON MICROSCOPYf_dihedral_angle_d4.1721153
ELECTRON MICROSCOPYf_chiral_restr0.0381058
ELECTRON MICROSCOPYf_plane_restr0.0011136

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