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- EMDB-47237: Dephosphorylated CFTR in 1:2 complex with PKA-C -

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Basic information

Entry
Database: EMDB / ID: EMD-47237
TitleDephosphorylated CFTR in 1:2 complex with PKA-C
Map dataDephosphorylated CFTR in 1:2 complex with PKA-C
Sample
  • Complex: dephosphorylated CFTR in 1:2 complex with PKA-C
    • Protein or peptide: cAMP-dependent protein kinase catalytic subunit alpha
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
    • Protein or peptide: cystic fibrosis transmembrane conductance regulator
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
KeywordsCFTR / PKA / complex / HYDROLASE
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 / CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / positive regulation of enamel mineralization / transepithelial water transport ...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 / CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / positive regulation of enamel mineralization / transepithelial water transport / Rap1 signalling / RHO GTPases regulate CFTR trafficking / Ion homeostasis / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / Loss of proteins required for interphase microtubule organization from the centrosome / Anchoring of the basal body to the plasma membrane / AURKA Activation by TPX2 / Factors involved in megakaryocyte development and platelet production / RET signaling / intracellular pH elevation / amelogenesis / Interleukin-3, Interleukin-5 and GM-CSF signaling / Recruitment of NuMA to mitotic centrosomes / chloride channel inhibitor activity / VEGFA-VEGFR2 Pathway / PKA activation / ATPase-coupled inorganic anion transmembrane transporter activity / MAPK6/MAPK4 signaling / GLI3 is processed to GLI3R by the proteasome / Regulation of PLK1 Activity at G2/M Transition / Hedgehog 'off' state / Golgi-associated vesicle membrane / multicellular organismal-level water homeostasis / cholesterol transport / bicarbonate transport / bicarbonate transmembrane transporter activity / membrane hyperpolarization / vesicle docking involved in exocytosis / chloride channel regulator activity / chloride transmembrane transporter activity / cAMP-dependent protein kinase / regulation of protein processing / cAMP-dependent protein kinase activity / protein localization to lipid droplet / cAMP-dependent protein kinase complex / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cellular response to cold / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / regulation of osteoblast differentiation / sperm capacitation / Mitochondrial protein degradation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / cholesterol biosynthetic process / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / protein kinase A regulatory subunit binding / chloride channel activity / RHOQ GTPase cycle / positive regulation of exocytosis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / mesoderm formation / sperm flagellum / plasma membrane raft / axoneme / ATPase-coupled transmembrane transporter activity / chloride channel complex / ABC-type transporter activity / postsynaptic modulation of chemical synaptic transmission / negative regulation of TORC1 signaling / cellular response to cAMP / 14-3-3 protein binding / regulation of proteasomal protein catabolic process / positive regulation of gluconeogenesis / cellular response to forskolin / protein serine/threonine/tyrosine kinase activity / cellular response to glucagon stimulus / chloride transmembrane transport / response to endoplasmic reticulum stress / protein export from nucleus / acrosomal vesicle / positive regulation of protein export from nucleus / PDZ domain binding / negative regulation of smoothened signaling pathway / isomerase activity / establishment of localization in cell / neural tube closure / positive regulation of cholesterol biosynthetic process / Defective CFTR causes cystic fibrosis / clathrin-coated endocytic vesicle membrane / cellular response to glucose stimulus / Late endosomal microautophagy / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / neuromuscular junction
Similarity search - Function
: / CFTR regulator domain / Cystic fibrosis TM conductance regulator (CFTR), regulator domain / Cystic fibrosis transmembrane conductance regulator / : / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / ABC transporter transmembrane region ...: / CFTR regulator domain / Cystic fibrosis TM conductance regulator (CFTR), regulator domain / Cystic fibrosis transmembrane conductance regulator / : / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / 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. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
cAMP-dependent protein kinase catalytic subunit alpha / Cystic fibrosis transmembrane conductance regulator
Similarity search - Component
Biological speciesBos taurus (domestic cattle) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.0 Å
AuthorsFiedorczuk K / Chen J / Csanady L
Funding support United States, 2 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
Cystic Fibrosis Foundation United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: The structures of protein kinase A in complex with CFTR: Mechanisms of phosphorylation and noncatalytic activation.
Authors: Karol Fiedorczuk / Iordan Iordanov / Csaba Mihályi / Andras Szollosi / László Csanády / Jue Chen /
Abstract: Protein kinase A (PKA) is a key regulator of cellular functions by selectively phosphorylating numerous substrates, including ion channels, enzymes, and transcription factors. It has long served as a ...Protein kinase A (PKA) is a key regulator of cellular functions by selectively phosphorylating numerous substrates, including ion channels, enzymes, and transcription factors. It has long served as a model system for understanding the eukaryotic kinases. Using cryoelectron microscopy, we present complex structures of the PKA catalytic subunit (PKA-C) bound to a full-length protein substrate, the cystic fibrosis transmembrane conductance regulator (CFTR)-an ion channel vital to human health. CFTR gating requires phosphorylation of its regulatory (R) domain. Unphosphorylated CFTR engages PKA-C at two locations, establishing two "catalytic stations" near to, but not directly involving, the R domain. This configuration, coupled with the conformational flexibility of the R domain, permits transient interactions of the eleven spatially separated phosphorylation sites. Furthermore, we determined two structures of the open-pore CFTR stabilized by PKA-C, providing a molecular basis to understand how PKA-C stimulates CFTR currents even in the absence of phosphorylation.
History
DepositionOct 8, 2024-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47237.png

Downloads & links

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Map

FileDownload / File: emd_47237.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDephosphorylated CFTR in 1:2 complex with PKA-C
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: 0.186
Minimum - Maximum-0.6650808 - 1.2825246
Average (Standard dev.)0.003947009 (±0.035633624)
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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Half map: half-map 1

Fileemd_47237_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_47237_half_map_2.map
Annotationhalf-map 2
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : dephosphorylated CFTR in 1:2 complex with PKA-C

EntireName: dephosphorylated CFTR in 1:2 complex with PKA-C
Components
  • Complex: dephosphorylated CFTR in 1:2 complex with PKA-C
    • Protein or peptide: cAMP-dependent protein kinase catalytic subunit alpha
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
    • Protein or peptide: cystic fibrosis transmembrane conductance regulator
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

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Supramolecule #1: dephosphorylated CFTR in 1:2 complex with PKA-C

SupramoleculeName: dephosphorylated CFTR in 1:2 complex with PKA-C / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 210 KDa

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Macromolecule #1: cAMP-dependent protein kinase catalytic subunit alpha

MacromoleculeName: cAMP-dependent protein kinase catalytic subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: cAMP-dependent protein kinase
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 40.677652 KDa
SequenceString: MGNAAAAKKG SEQESVKEFL AKAKEDFLKK WENPAQNTAH LDQFERIKTL GTGSFGRVML VKHMETGNHY AMKILDKQKV VKLKQIEHT LNEKRILQAV NFPFLVKLEF SFKDNSNLYM VMEYVPGGEM FSHLRRIGRF SEPHARFYAA QIVLTFEYLH S LDLIYRDL ...String:
MGNAAAAKKG SEQESVKEFL AKAKEDFLKK WENPAQNTAH LDQFERIKTL GTGSFGRVML VKHMETGNHY AMKILDKQKV VKLKQIEHT LNEKRILQAV NFPFLVKLEF SFKDNSNLYM VMEYVPGGEM FSHLRRIGRF SEPHARFYAA QIVLTFEYLH S LDLIYRDL KPENLLIDQQ GYIQVTDFGF AKRVKGRTWT LCGTPEYLAP EIILSKGYNK AVDWWALGVL IYEMAAGYPP FF ADQPIQI YEKIVSGKVR FPSHFSSDLK DLLRNLLQVD LTKRFGNLKN GVNDIKNHKW FATTDWIAIY QRKVEAPFIP KFK GPGDTS NFDDYEEEEI RVSINEKCGK EFSEF

UniProtKB: cAMP-dependent protein kinase catalytic subunit alpha

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Macromolecule #2: Cystic fibrosis transmembrane conductance regulator

MacromoleculeName: Cystic fibrosis transmembrane conductance regulator / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: channel-conductance-controlling ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 168.335453 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 SEQGEAILPR ISVISTGPTL QARRRQSVLN LMTHSVNQGQ NIHRKTTAST RKVSLAPQA NLTELDIYSR RLSQETGLEI SEEINEEDLK ECFFDDMESI PAVTTWNTYL RYITVHKSLI FVLIWCLVIF LAEVAASLVV LWLLGNTPL QDKGNSTHSR NNSYAVIITS TSSYYVFYIY VGVADTLLAM GFFRGLPLVH TLITVSKILH HKMLHSVLQA P MSTLNTLK AGGILNRFSK DIAILDDLLP LTIFDFIQLL LIVIGAIAVV AVLQPYIFVA TVPVIVAFIM LRAYFLQTSQ QL KQLESEG RSPIFTHLVT SLKGLWTLRA FGRQPYFETL FHKALNLHTA NWFLYLSTLR WFQMRIEMIF VIFFIAVTFI SIL TTGEGE GRVGIILTLA MNIMSTLQWA VNSSIDVDSL MRSVSRVFKF IDMPTEGKPT KSTKPYKNGQ LSKVMIIENS HVKK DDIWP SGGQMTVKDL TAKYTEGGNA ILENISFSIS PGQRVGLLGR TGSGKSTLLS AFLRLLNTEG EIQIDGVSWD SITLQ QWRK AFGVIPQKVF IFSGTFRKNL DPYEQWSDQE IWKVADEVGL RSVIEQFPGK LDFVLVDGGC VLSHGHKQLM CLARSV LSK AKILLLDEPS AHLDPVTYQI IRRTLKQAFA DCTVILCEHR IEAMLECQQF LVIEENKVRQ YDSIQKLLNE RSLFRQA IS PSDRVKLFPH RNSSKCKSKP QIAALKEETE EEVQDTRL

UniProtKB: Cystic fibrosis transmembrane conductance regulator

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Macromolecule #3: cystic fibrosis transmembrane conductance regulator

MacromoleculeName: cystic fibrosis transmembrane conductance regulator / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.635006 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / type: ligand / ID: 5 / Number of copies: 1 / Formula: ANP
Molecular weightTheoretical: 506.196 Da
Chemical component information

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*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 / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 52.0 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:

8516

Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 29826
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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