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- EMDB-28160: The complex of phosphorylated human delta F508 cystic fibrosis tr... -

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Entry
Database: EMDB / ID: EMD-28160
TitleThe complex of phosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) with elexacaftor (VX-445), lumacaftor (VX-809) and ATP/Mg
Map dataDelta 508 cystic fibrosis transmembrane conductance regulator (d508CFTR) in complex with lumacaftor, elexacaftor and ATP/Mg
Sample
  • Complex: The complex of phosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) with elexacaftor (VX-445), lumacaftor (VX-809) and ATP/Mg
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
  • Ligand: MAGNESIUM ION
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: CHOLESTEROL
  • Ligand: DODECANE
  • Ligand: Lumacaftor
  • Ligand: (6P)-N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide
KeywordsABC transporter / ion channel / folding correction / membrane protein / ATP-Binding Protein
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 / ATPase-coupled inorganic anion transmembrane transporter activity / chloride channel inhibitor activity / Golgi-associated vesicle membrane / multicellular organismal-level water homeostasis / membrane hyperpolarization / cholesterol transport / bicarbonate transport / bicarbonate transmembrane transporter activity / vesicle docking involved in exocytosis / chloride channel regulator activity / chloride transmembrane transporter activity / sperm capacitation / chloride channel activity / RHOQ GTPase cycle / cholesterol biosynthetic process / 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 / chloride transmembrane transport / isomerase activity / response to endoplasmic reticulum stress / establishment of localization in cell / PDZ domain binding / Defective CFTR causes cystic fibrosis / Late endosomal microautophagy / clathrin-coated endocytic vesicle membrane / ABC-family proteins mediated transport / recycling endosome / transmembrane transport / Aggrephagy / Chaperone Mediated Autophagy / recycling endosome membrane / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / early endosome membrane / protein-folding chaperone binding / 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 / cytoplasm / cytosol
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: 2.8 Å
AuthorsFiedorczuk K / Chen J
Funding support United States, 2 items
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 15, 2022-
Header (metadata) releaseOct 19, 2022-
Map releaseOct 19, 2022-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28160.png

Downloads & links

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Map

FileDownload / File: emd_28160.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDelta 508 cystic fibrosis transmembrane conductance regulator (d508CFTR) in complex with lumacaftor, elexacaftor and ATP/Mg
Voxel sizeX=Y=Z: 0.676 Å
Density
Contour LevelBy AUTHOR: 0.012
Minimum - Maximum-0.027803082 - 0.070136465
Average (Standard dev.)-0.0000025493418 (±0.0017457459)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 297.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_28160_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 1

Fileemd_28160_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_28160_half_map_2.map
Annotationhalf map 2
Projections & Slices
AxesZYX

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Sample components

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Entire : The complex of phosphorylated human delta F508 cystic fibrosis tr...

EntireName: The complex of phosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) with elexacaftor (VX-445), lumacaftor (VX-809) and ATP/Mg
Components
  • Complex: The complex of phosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) with elexacaftor (VX-445), lumacaftor (VX-809) and ATP/Mg
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
  • Ligand: MAGNESIUM ION
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: CHOLESTEROL
  • Ligand: DODECANE
  • Ligand: Lumacaftor
  • Ligand: (6P)-N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide

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Supramolecule #1: The complex of phosphorylated human delta F508 cystic fibrosis tr...

SupramoleculeName: The complex of phosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) with elexacaftor (VX-445), lumacaftor (VX-809) and ATP/Mg
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 168 KDa

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Macromolecule #1: Cystic fibrosis transmembrane conductance regulator

MacromoleculeName: Cystic fibrosis transmembrane conductance regulator / type: protein_or_peptide / ID: 1
Details: Expressed construct is human CFTR with F508 deletion and E1371Q substitution
Number of copies: 1 / Enantiomer: LEVO / EC number: channel-conductance-controlling ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 168.187297 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 NIIGVSYDEY RYRSVIKACQ LEEDISKFAE KDNIVLGEGG ITLSGGQRAR ISLARA VYK DADLYLLDSP FGYLDVLTEK EIFESCVCKL MANKTRILVT SKMEHLKKAD KILILHEGSS YFYGTFSELQ NLQPDFS SK LMGCDSFDQF SAERRNSILT ETLHRFSLEG DAPVSWTETK KQSFKQTGEF GEKRKNSILN PINSIRKFSI VQKTPLQM N GIEEDSDEPL ERRLSLVPDS EQGEAILPRI SVISTGPTLQ ARRRQSVLNL MTHSVNQGQN IHRKTTASTR KVSLAPQAN LTELDIYSRR LSQETGLEIS EEINEEDLKE CFFDDMESIP AVTTWNTYLR YITVHKSLIF VLIWCLVIFL AEVAASLVVL WLLGNTPLQ DKGNSTHSRN NSYAVIITST SSYYVFYIYV GVADTLLAMG FFRGLPLVHT LITVSKILHH KMLHSVLQAP M STLNTLKA GGILNRFSKD IAILDDLLPL TIFDFIQLLL IVIGAIAVVA VLQPYIFVAT VPVIVAFIML RAYFLQTSQQ LK QLESEGR SPIFTHLVTS LKGLWTLRAF GRQPYFETLF HKALNLHTAN WFLYLSTLRW FQMRIEMIFV IFFIAVTFIS ILT TGEGEG RVGIILTLAM NIMSTLQWAV NSSIDVDSLM RSVSRVFKFI DMPTEGKPTK STKPYKNGQL SKVMIIENSH VKKD DIWPS GGQMTVKDLT AKYTEGGNAI LENISFSISP GQRVGLLGRT GSGKSTLLSA FLRLLNTEGE IQIDGVSWDS ITLQQ WRKA FGVIPQKVFI FSGTFRKNLD PYEQWSDQEI WKVADEVGLR SVIEQFPGKL DFVLVDGGCV LSHGHKQLMC LARSVL SKA KILLLDQPSA HLDPVTYQII RRTLKQAFAD CTVILCEHRI EAMLECQQFL VIEENKVRQY DSIQKLLNER SLFRQAI SP SDRVKLFPHR NSSKCKSKPQ IAALKEETEE EVQDTRL

UniProtKB: Cystic fibrosis transmembrane conductance regulator

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Macromolecule #2: Cystic fibrosis transmembrane conductance regulator

MacromoleculeName: Cystic fibrosis transmembrane conductance regulator / type: protein_or_peptide / ID: 2
Details: R-domain of del508CFTR (UNP:P13569). Expressed construct is human CFTR with F508 deletion and E1371Q substitution.
Number of copies: 1 / Enantiomer: LEVO / EC number: channel-conductance-controlling ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.464797 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)

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Macromolecule #3: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 3 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #4: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

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

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #6: DODECANE

MacromoleculeName: DODECANE / type: ligand / ID: 6 / Number of copies: 1 / Formula: D12
Molecular weightTheoretical: 170.335 Da
Chemical component information

ChemComp-D12:
DODECANE

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Macromolecule #7: Lumacaftor

MacromoleculeName: Lumacaftor / type: ligand / ID: 7 / Number of copies: 1 / Formula: VX8
Molecular weightTheoretical: 452.407 Da
Chemical component information

ChemComp-VX8:
Lumacaftor

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Macromolecule #8: (6P)-N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluor...

MacromoleculeName: (6P)-N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide
type: ligand / ID: 8 / Number of copies: 1 / Formula: WJX
Molecular weightTheoretical: 597.653 Da
Chemical component information

ChemComp-WJX:
(6P)-N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide / medication*YM

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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 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
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:

7svd

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 41548
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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