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- EMDB-28161: The complex of phosphorylated human delta F508 cystic fibrosis tr... -

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Entry
Database: EMDB / ID: EMD-28161
TitleThe complex of phosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) with Trikafta [elexacaftor (VX-445), tezacaftor (VX-661), ivacaftor (VX-770)] and ATP/Mg
Map datadel508CFTR phosphorylated in complex with Trikafta (tezacaftor, ivacaftor, elexacaftor) and ATP/Mg
Sample
  • Complex: The complex of phosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) with Trikafta [elexacaftor (VX-445), tezacaftor (VX-661), ivacaftor (VX-770)] 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: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
  • 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
  • Ligand: Tezacaftor
KeywordsABC transporter / ion channel / Trikafta / folding correction / membrane protein / ATP-Binding Protein
Function / homology
Function and homology information


positive regulation of voltage-gated chloride 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 / amelogenesis / intracellular pH elevation ...positive regulation of voltage-gated chloride 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 / amelogenesis / intracellular pH elevation / chloride channel inhibitor activity / : / Golgi-associated vesicle membrane / multicellular organismal-level water homeostasis / cholesterol transport / bicarbonate transport / bicarbonate transmembrane transporter activity / chloride channel regulator activity / vesicle docking involved in exocytosis / membrane hyperpolarization / chloride transmembrane transporter activity / sperm capacitation / cholesterol biosynthetic process / RHOQ GTPase cycle / chloride channel activity / positive regulation of exocytosis / ATPase-coupled transmembrane transporter activity / chloride channel complex / positive regulation of insulin secretion involved in cellular response to glucose stimulus / ABC-type transporter activity / 14-3-3 protein binding / cellular response to forskolin / chloride transmembrane transport / response to endoplasmic reticulum stress / cellular response to cAMP / PDZ domain binding / establishment of localization in cell / clathrin-coated endocytic vesicle membrane / Defective CFTR causes cystic fibrosis / Late endosomal microautophagy / recycling endosome / ABC-family proteins mediated transport / transmembrane transport / recycling endosome membrane / Chaperone Mediated Autophagy / Aggrephagy / 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 / protein-containing complex / ATP hydrolysis activity / ATP binding / nucleus / membrane / 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 ...: / 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: 3.0 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-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28161.png

Downloads & links

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Map

FileDownload / File: emd_28161.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationdel508CFTR phosphorylated in complex with Trikafta (tezacaftor, ivacaftor, elexacaftor) and ATP/Mg
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.68 Å/pix.
x 440 pix.
= 297.44 Å		0.68 Å/pix.
x 440 pix.
= 297.44 Å		0.68 Å/pix.
x 440 pix.
= 297.44 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.676 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.037148785 - 0.063744895
Average (Standard dev.)0.000038671653 (±0.0017184885)
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_28161_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 of del508CFTR phosphorylated in complex...

Fileemd_28161_half_map_1.map
AnnotationHalf map 1 of del508CFTR phosphorylated in complex with Trikafta (tezacaftor, lumacaftor, elexacaftor) and ATP/Mg
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2 of del508CFTR phosphorylated in complex...

Fileemd_28161_half_map_2.map
AnnotationHalf map 2 of del508CFTR phosphorylated in complex with Trikafta (tezacaftor, lumacaftor, elexacaftor) and ATP/Mg
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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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 Trikafta [elexacaftor (VX-445), tezacaftor (VX-661), ivacaftor (VX-770)] and ATP/Mg
Components
  • Complex: The complex of phosphorylated human delta F508 cystic fibrosis transmembrane conductance regulator (CFTR) with Trikafta [elexacaftor (VX-445), tezacaftor (VX-661), ivacaftor (VX-770)] 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: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
  • 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
  • Ligand: Tezacaftor

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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 Trikafta [elexacaftor (VX-445), tezacaftor (VX-661), ivacaftor (VX-770)] 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: human CFTR with F508 deletion and E1370Q 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: 1.379692 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
(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: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-...

MacromoleculeName: N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
type: ligand / ID: 7 / Number of copies: 1 / Formula: VX7
Molecular weightTheoretical: 392.491 Da
Chemical component information

ChemComp-VX7:
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

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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

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Macromolecule #9: Tezacaftor

MacromoleculeName: Tezacaftor / type: ligand / ID: 9 / Number of copies: 1 / Formula: CV6
Molecular weightTheoretical: 520.498 Da
Chemical component information

ChemComp-CV6:
Tezacaftor

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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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

25447

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 243682
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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