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- EMDB-0606: Complex of human cystic fibrosis transmembrane conductance regula... -

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Basic information

Entry
Database: EMDB / ID: EMD-0606
TitleComplex of human cystic fibrosis transmembrane conductance regulator (CFTR) and GLPG1837
Map data
SampleComplex of human cystic fibrosis transmembrane conductance regulator (CFTR) and GLPG1837
  • Cystic fibrosis transmembrane conductance regulator
  • Unknown Peptide
  • (ligand) x 5
Function / homology
Function and homology information


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 / Golgi-associated vesicle membrane / bicarbonate transmembrane transporter activity / multicellular organismal water homeostasis ...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 / Golgi-associated vesicle membrane / bicarbonate transmembrane transporter activity / multicellular organismal water homeostasis / chloride channel regulator activity / chloride transmembrane transporter activity / chloride channel inhibitor activity / vesicle docking involved in exocytosis / membrane hyperpolarization / cholesterol transport / chloride channel activity / chloride channel complex / cellular response to forskolin / chloride transmembrane transport / positive regulation of exocytosis / cholesterol biosynthetic process / sperm capacitation / ATPase-coupled transmembrane transporter activity / positive regulation of insulin secretion involved in cellular response to glucose stimulus / isomerase activity / response to endoplasmic reticulum stress / clathrin-coated vesicle membrane / PDZ domain binding / cellular response to cAMP / recycling endosome / recycling endosome membrane / bicarbonate transport / lysosomal membrane / transmembrane transport / early endosome membrane / membrane organization / chaperone binding / apical plasma membrane / early endosome / endosome membrane / protein deubiquitination / ATPase activity / endoplasmic reticulum membrane / cell surface / integral component of plasma membrane / enzyme binding / protein-containing complex / membrane / integral component of membrane / ATP binding / plasma membrane / nucleus / cytosol / cytoplasm
ABC transporter-like / ABC transporter type 1, transmembrane domain superfamily / P-loop containing nucleoside triphosphate hydrolase / CFTR regulator domain / ABC transporter, conserved site / ABC transporter type 1, transmembrane domain / Cystic fibrosis transmembrane conductance regulator / AAA+ ATPase domain
Cystic fibrosis transmembrane conductance regulator
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsZhang Z / Liu F / Chen J / Levit A / Shoichet B
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Science / Year: 2019
Title: Structural identification of a hotspot on CFTR for potentiation.
Authors: Fangyu Liu / Zhe Zhang / Anat Levit / Jesper Levring / Kouki K Touhara / Brian K Shoichet / Jue Chen /
Abstract: Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve ...Cystic fibrosis is a fatal disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Two main categories of drugs are being developed: correctors that improve folding of CFTR and potentiators that recover the function of CFTR. Here, we report two cryo-electron microscopy structures of human CFTR in complex with potentiators: one with the U.S. Food and Drug Administration (FDA)-approved drug ivacaftor at 3.3-angstrom resolution and the other with an investigational drug, GLPG1837, at 3.2-angstrom resolution. These two drugs, although chemically dissimilar, bind to the same site within the transmembrane region. Mutagenesis suggests that in both cases, hydrogen bonds provided by the protein are important for drug recognition. The molecular details of how ivacaftor and GLPG1837 interact with CFTR may facilitate structure-based optimization of therapeutic compounds.
Validation ReportPDB-ID: 6o1v

SummaryFull reportAbout validation report
History
Header (metadata) releaseNov 21, 2018-
Map releaseNov 21, 2018-
DepositionFeb 21, 2019-
UpdateNov 27, 2019-
Current statusNov 27, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.61
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.61
  • Imaged by UCSF Chimera
  • Download
  • Surface view with fitted model
  • Atomic models: PDB-6o1v
  • Surface level: 0.61
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_0606.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.03 Å/pix.
x 300 pix.
= 309. Å
1.03 Å/pix.
x 300 pix.
= 309. Å
1.03 Å/pix.
x 300 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 LevelBy AUTHOR: 0.61 / Movie #1: 0.61
Minimum - Maximum-1.4519366 - 2.5725448
Average (Standard dev.)0.0021192075 (±0.062607445)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 309.0 Å
α=β=γ: 90.0 °

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/NZ304304304
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-1.4522.5730.002

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Supplemental data

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Sample components

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Entire Complex of human cystic fibrosis transmembrane conductance regula...

EntireName: Complex of human cystic fibrosis transmembrane conductance regulator (CFTR) and GLPG1837
Number of components: 8

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Component #1: protein, Complex of human cystic fibrosis transmembrane conductan...

ProteinName: Complex of human cystic fibrosis transmembrane conductance regulator (CFTR) and GLPG1837
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, Unknown Peptide

ProteinName: Unknown Peptide / 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, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[...

LigandName: N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.34842 kDa

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Component #5: ligand, MAGNESIUM ION

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

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Component #6: ligand, ADENOSINE-5'-TRIPHOSPHATE

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

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Component #7: 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 #8: 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.: 5.5 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: 510483
3D reconstructionSoftware: FREALIGN / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Modeling #1Refinement space: RECIPROCAL
Input PDB model: 6MSM
Overall bvalue: 150
Output model

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