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- EMDB-29637: Dehosphorylated, ATP-bound human cystic fibrosis transmembrane co... -

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Basic information

Entry
Database: EMDB / ID: EMD-29637
TitleDehosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
Map dataDephosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
Sample
  • Complex: Dephosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
  • Ligand: MAGNESIUM ION
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
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 cAMP / cellular response to forskolin / isomerase activity / chloride transmembrane transport / response to endoplasmic reticulum stress / PDZ domain binding / establishment of localization in cell / Defective CFTR causes cystic fibrosis / Late endosomal microautophagy / clathrin-coated endocytic vesicle membrane / 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
Cystic fibrosis transmembrane conductance regulator
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsLevring J / Terry DS / Kilic Z / Fitzgerald GA / Blanchard SC / Chen J
Funding support United States, 2 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM079238 United States
CitationJournal: Nature / Year: 2023
Title: CFTR function, pathology and pharmacology at single-molecule resolution.
Authors: Jesper Levring / Daniel S Terry / Zeliha Kilic / Gabriel Fitzgerald / Scott C Blanchard / Jue Chen /
Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes. Alterations in CFTR cause cystic fibrosis, a ...The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes. Alterations in CFTR cause cystic fibrosis, a fatal disease without a cure. Electrophysiological properties of CFTR have been analysed for decades. The structure of CFTR, determined in two globally distinct conformations, underscores its evolutionary relationship with other ATP-binding cassette transporters. However, direct correlations between the essential functions of CFTR and extant structures are lacking at present. Here we combine ensemble functional measurements, single-molecule fluorescence resonance energy transfer, electrophysiology and kinetic simulations to show that the two nucleotide-binding domains (NBDs) of human CFTR dimerize before channel opening. CFTR exhibits an allosteric gating mechanism in which conformational changes within the NBD-dimerized channel, governed by ATP hydrolysis, regulate chloride conductance. The potentiators ivacaftor and GLPG1837 enhance channel activity by increasing pore opening while NBDs are dimerized. Disease-causing substitutions proximal (G551D) or distal (L927P) to the ATPase site both reduce the efficiency of NBD dimerization. These findings collectively enable the framing of a gating mechanism that informs on the search for more efficacious clinical therapies.
History
DepositionJan 29, 2023-
Header (metadata) releaseMar 29, 2023-
Map releaseMar 29, 2023-
UpdateMay 3, 2023-
Current statusMay 3, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29637.png

Downloads & links

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Map

FileDownload / File: emd_29637.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDephosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
Voxel sizeX=Y=Z: 1.03 Å
Density
Contour LevelBy AUTHOR: 0.027
Minimum - Maximum-0.04568406 - 0.08411895
Average (Standard dev.)-8.062291e-05 (±0.0020086812)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 395.52 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map 1 for Dephosphorylated, ATP-bound human cystic...

Fileemd_29637_half_map_1.map
AnnotationHalf map 1 for Dephosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2 for Dephosphorylated, ATP-bound human cystic...

Fileemd_29637_half_map_2.map
AnnotationHalf map 2 for Dephosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Dephosphorylated, ATP-bound human cystic fibrosis transmembrane c...

EntireName: Dephosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
Components
  • Complex: Dephosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
  • Ligand: MAGNESIUM ION
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE

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Supramolecule #1: Dephosphorylated, ATP-bound human cystic fibrosis transmembrane c...

SupramoleculeName: Dephosphorylated, ATP-bound human cystic fibrosis transmembrane conductance regulator (CFTR)
type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Cystic fibrosis transmembrane conductance regulator

MacromoleculeName: Cystic fibrosis transmembrane conductance regulator / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: channel-conductance-controlling ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 168.859062 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MQRSPLEKAS VVSKLFFSWT RPILRKGYRQ RLELSDIYQI PSVDSADNLS EKLEREWDRE LASKKNPKLI NALRRCFFWR FMFYGIFLY LGEVTKAVQP LLLGRIIASY DPDNKEERSI AIYLGIGLCL LFIVRTLLLH PAIFGLHHIG MQMRIAMFSL I YKKTLKLS ...String:
MQRSPLEKAS VVSKLFFSWT RPILRKGYRQ RLELSDIYQI PSVDSADNLS EKLEREWDRE LASKKNPKLI NALRRCFFWR FMFYGIFLY LGEVTKAVQP LLLGRIIASY DPDNKEERSI AIYLGIGLCL LFIVRTLLLH PAIFGLHHIG MQMRIAMFSL I YKKTLKLS SRVLDKISIG QLVSLLSNNL NKFDEGLALA HFVWIAPLQV ALLMGLIWEL LQASAFCGLG FLIVLALFQA GL GRMMMKY RDQRAGKISE RLVITSEMIE NIQSVKAYCW EEAMEKMIEN LRQTELKLTR KAAYVRYFNS SAFFFSGFFV VFL SVLPYA LIKGIILRKI FTTISFCIVL RMAVTRQFPW AVQTWYDSLG AINKIQDFLQ KQEYKTLEYN LTTTEVVMEN VTAF WEEGF GELFEKAKQN NNNRKTSNGD DSLFFSNFSL LGTPVLKDIN FKIERGQLLA VAGSTGAGKT SLLMVIMGEL EPSEG KIKH SGRISFCSQF SWIMPGTIKE NIIFGVSYDE YRYRSVIKAC QLEEDISKFA EKDNIVLGEG GITLSGGQRA RISLAR AVY KDADLYLLDS PFGYLDVLTE KEIFESCVCK LMANKTRILV TSKMEHLKKA DKILILHEGS SYFYGTFSEL QNLQPDF SS KLMGCDSFDQ FSAERRNSIL TETLHRFSLE GDAPVSWTET KKQSFKQTGE FGEKRKNSIL NPINSIRKFS IVQKTPLQ M NGIEEDSDEP LERRLSLVPD SEQGEAILP(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)L NLMTHSVNQG QNIHRKTTAS TRKVSLAPQA NLTE LDIYS RRLSQETGLE ISEEINEEDL KECFFDDMES IPAVTTWNTY LRYITVHKSL IFVLIWCLVI FLAEVAASLV VLWLL GNTP LQDKGNSTHS RNNSYAVIIT STSSYYVFYI YVGVADTLLA MGFFRGLPLV HTLITVSKIL HHKMLHSVLQ APMSTL NTL KAGGILNRFS KDIAILDDLL PLTIFDFIQL LLIVIGAIAV VAVLQPYIFV ATVPVIVAFI MLRAYFLQTS QQLKQLE SE GRSPIFTHLV TSLKGLWTLR AFGRQPYFET LFHKALNLHT ANWFLYLSTL RWFQMRIEMI FVIFFIAVTF ISILTTGE G EGRVGIILTL AMNIMSTLQW AVNSSIDVDS LMRSVSRVFK FIDMPTEGKP TKSTKPYKNG QLSKVMIIEN SHVKKDDIW PSGGQMTVKD LTAKYTEGGN AILENISFSI SPGQRVGLLG RTGSGKSTLL SAFLRLLNTE GEIQIDGVSW DSITLQQWRK AFGVIPQKV FIFSGTFRKN LDPYEQWSDQ EIWKVADEVG LRSVIEQFPG KLDFVLVDGG CVLSHGHKQL MCLARSVLSK A KILLLDEP SAHLDPVTYQ IIRRTLKQAF ADCTVILCEH RIEAMLECQQ FLVIEENKVR QYDSIQKLLN ERSLFRQAIS PS DRVKLFP HRNSSKCKSK PQIAALKEET EEEVQDTRLS NSLEVLFQ

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Macromolecule #2: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 2 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #3: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration5.5 mg/mL
BufferpH: 7.2
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 75.4 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5uak

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 157629

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