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- PDB-6msm: Phosphorylated, ATP-bound human cystic fibrosis transmembrane con... -

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Basic information

Entry
Database: PDB / ID: 6msm
TitlePhosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
Components
  • Cystic fibrosis transmembrane conductance regulator
  • Piece of Molecule-1
KeywordsHYDROLASE / ABC transporter / anion channel / cystic fibrosis / membrane protein
Function / homologyABC transporter transmembrane region / Cystic fibrosis TM conductance regulator (CFTR), regulator domain / ABC transporter type 1, transmembrane domain / ABC transporter, conserved site / CFTR regulator domain / P-loop containing nucleoside triphosphate hydrolase / ABC transporter type 1, transmembrane domain superfamily / ABC transporter / ABC transporter-like / ABC transporters family signature. ...ABC transporter transmembrane region / Cystic fibrosis TM conductance regulator (CFTR), regulator domain / ABC transporter type 1, transmembrane domain / ABC transporter, conserved site / CFTR regulator domain / P-loop containing nucleoside triphosphate hydrolase / ABC transporter type 1, transmembrane domain superfamily / ABC transporter / ABC transporter-like / ABC transporters family signature. / AAA+ ATPase domain / ATP-binding cassette, ABC transporter-type domain profile. / ABC transporter integral membrane type-1 fused domain profile. / ABC-family proteins mediated transport / RHO GTPases regulate CFTR trafficking / Defective CFTR causes cystic fibrosis / Ub-specific processing proteases / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / Cystic fibrosis transmembrane conductance regulator / ATPase-coupled anion transmembrane transporter activity / Sec61 translocon complex binding / positive regulation of cyclic nucleotide-gated ion channel activity / positive regulation of voltage-gated chloride channel activity / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / transepithelial water transport / intracellular pH elevation / bicarbonate transmembrane transporter activity / multicellular organismal water homeostasis / Golgi-associated vesicle membrane / chloride channel regulator activity / chloride transmembrane transporter activity / chloride channel inhibitor activity / vesicle docking involved in exocytosis / chloride channel activity / chloride channel complex / membrane hyperpolarization / cholesterol transport / chloride transmembrane transport / cellular response to forskolin / positive regulation of exocytosis / ATPase activity, coupled to transmembrane movement of substances / positive regulation of insulin secretion involved in cellular response to glucose stimulus / cholesterol biosynthetic process / sperm capacitation / recycling endosome / clathrin-coated vesicle membrane / cellular response to cAMP / PDZ domain binding / transmembrane transport / recycling endosome membrane / lysosomal membrane / bicarbonate transport / membrane organization / early endosome membrane / chaperone binding / apical plasma membrane / endosome membrane / early endosome / ATPase activity / protein deubiquitination / endoplasmic reticulum membrane / integral component of plasma membrane / cell surface / enzyme binding / protein-containing complex / membrane / integral component of membrane / ATP binding / plasma membrane / nucleus / cytosol / cytoplasm / Cystic fibrosis transmembrane conductance regulator
Function and homology information
Specimen sourceHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 3.2 Å resolution
AuthorsZhang, Z. / Liu, F. / Chen, J.
CitationJournal: Proc. Natl. Acad. Sci. U.S.A. / Year: 2018
Title: Molecular structure of the ATP-bound, phosphorylated human CFTR.
Authors: Zhe Zhang / Fangyu Liu / Jue Chen
Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel important in maintaining proper functions of the lung, pancreas, and intestine. The activity of CFTR is regulated by ...The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel important in maintaining proper functions of the lung, pancreas, and intestine. The activity of CFTR is regulated by ATP and protein kinase A-dependent phosphorylation. To understand the conformational changes elicited by phosphorylation and ATP binding, we present here the structure of phosphorylated, ATP-bound human CFTR, determined by cryoelectron microscopy to 3.2-Å resolution. This structure reveals the position of the R domain after phosphorylation. By comparing the structures of human CFTR and zebrafish CFTR determined under the same condition, we identified common features essential to channel gating. The differences in their structures indicate plasticity permitted in evolution to achieve the same function. Finally, the structure of CFTR provides a better understanding of why the G178R, R352Q, L927P, and G970R/D mutations would impede conformational changes of CFTR and lead to cystic fibrosis.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Oct 16, 2018 / Release: Nov 21, 2018
RevisionDateData content typeGroupCategoryItemProviderType
1.0Nov 21, 2018Structure modelrepositoryInitial release
1.1Dec 5, 2018Structure modelData collection / Database referencescitation_citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title

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Assembly

Deposited unit
A: Cystic fibrosis transmembrane conductance regulator
B: Piece of Molecule-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)176,06712
Polyers170,8172
Non-polymers5,25010
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
DetailsThe assembly is a monomer, since chain B is a part of Molecule-1

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Components

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Protein/peptide , 2 types, 2 molecules AB

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


Mass: 169352.594 Da / Num. of mol.: 1 / Mutation: E1371Q / Source: (gene. exp.) Homo sapiens (human)
Gene: CFTR, ABCC7Cystic fibrosis transmembrane conductance regulator
Production host: Homo sapiens (human)
References: UniProt: P13569, channel-conductance-controlling ATPase
#2: Protein/peptide Piece of Molecule-1


Mass: 1464.797 Da / Num. of mol.: 1 / Details: This is a part of Chain A / Source: (gene. exp.) Homo sapiens (human)
Gene: CFTR, ABCC7Cystic fibrosis transmembrane conductance regulator
Production host: Homo sapiens (human)

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Non-polymers , 4 types, 10 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Formula: Mg / Magnesium
#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 2 / Formula: C10H16N5O13P3 / Adenosine triphosphate / Comment: ATP (energy-carrying molecule) *YM
#5: Chemical
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 5 / Formula: C42H82NO8P / POPC
#6: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Formula: C27H46O / Cholesterol

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: human cystic fibrosis transmembrane conductance regulator (CFTR)
Type: COMPLEX / Entity ID: 1, 2 / Source: RECOMBINANT
Molecular weightValue: 0.168 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Cell: HEK293S GnTI- / Organism: Homo sapiens (human) / Plasmid: BacMam
Buffer solutionpH: 7.5
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationInstrument: FEI VITROBOT MARK I / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 kelvins

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyMicroscope model: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 1.51 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: NONE
SymmetryPoint symmetry: C1
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 677308 / Symmetry type: POINT

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