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- EMDB-9230: Phosphorylated, ATP-bound human cystic fibrosis transmembrane con... -

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Basic information

Entry
Database: EMDB / ID: 9230
TitlePhosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)Phosphorylation
Map data3.2A frealign refined map with -50A2 b-factor sharpening
Samplehuman cystic fibrosis transmembrane conductance regulator (CFTR)
  • Cystic fibrosis transmembrane conductance regulator
  • Piece of Molecule-1
  • (ligand) x 4
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
SourceHomo sapiens (human)
Methodsingle 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 ReportPDB-ID: 6msm

SummaryFull reportAbout validation report
DateDeposition: Oct 16, 2018 / Header (metadata) release: Nov 21, 2018 / Map release: Nov 21, 2018 / Last update: Nov 21, 2018

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.5
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6msm
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_9230.map.gz (map file in CCP4 format, 108001 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
300 pix
1.03 Å/pix.
= 309. Å
300 pix
1.03 Å/pix.
= 309. Å
300 pix
1.03 Å/pix.
= 309. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.03 Å
Density
Contour Level:0.5 (by author), 0.5 (movie #1):
Minimum - Maximum-1.3069118 - 2.3530545
Average (Standard dev.)0.002236153 (0.056431342)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions300300300
Origin0.00.00.0
Limit299.0299.0299.0
Spacing300300300
CellA=B=C: 309.0 Å
α=β=γ: 90.0 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.031.031.03
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z309.000309.000309.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ240240240
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-1.3072.3530.002

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Supplemental data

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Sample components

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Entire human cystic fibrosis transmembrane conductance regulator (CFTR)

EntireName: human cystic fibrosis transmembrane conductance regulator (CFTR)
Number of components: 7

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Component #1: protein, human cystic fibrosis transmembrane conductance regulato...

ProteinName: human cystic fibrosis transmembrane conductance regulator (CFTR)
Recombinant expression: No
MassTheoretical: 168 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human) / Vector: BacMam / Cell of expression system: HEK293S GnTI-

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Component #2: protein, Cystic fibrosis transmembrane conductance regulator

ProteinName: Cystic fibrosis transmembrane conductance regulator / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 169.352594 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, Piece of Molecule-1

ProteinName: Piece of Molecule-1 / Details: This is a part of Chain A / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 1.464797 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #4: ligand, MAGNESIUM ION

LigandName: MAGNESIUM ION / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 2.430505 MDa

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Component #5: ligand, ADENOSINE-5'-TRIPHOSPHATE

LigandName: ADENOSINE-5'-TRIPHOSPHATE / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 0.507181 kDa

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Component #6: ligand, (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propy...

LigandName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
Number of Copies: 5 / Recombinant expression: No
MassTheoretical: 0.760076 kDa

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Component #7: ligand, CHOLESTEROL

LigandName: CHOLESTEROL / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.386654 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: particle / Method: cryo EM
Sample solutionSpecimen conc.: 5 mg/ml / pH: 7.5
Support filmunspecified
VitrificationInstrument: FEI VITROBOT MARK I / Cryogen name: ETHANE / Temperature: 298 K / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 1.51 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 677308
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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