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- EMDB-72508: BS3-crosslinked Smoothened/PKA-C complex -

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Basic information

Entry
Database: EMDB / ID: EMD-72508
TitleBS3-crosslinked Smoothened/PKA-C complex
Map data
Sample
  • Complex: BS3-crosslinked Smoothened/PKA-C complex
    • Protein or peptide: mouse Smoothened 64-674
    • Protein or peptide: native-source bovine PKA-C
KeywordsHedgehog signaling / SIGNALING PROTEIN
Function / homology
Function and homology information


regulation of localization / response to inositol / pancreas morphogenesis / BBSome-mediated cargo-targeting to cilium / negative regulation of hair follicle development / central nervous system neuron differentiation / ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / regulation of heart morphogenesis / negative regulation of epithelial cell differentiation ...regulation of localization / response to inositol / pancreas morphogenesis / BBSome-mediated cargo-targeting to cilium / negative regulation of hair follicle development / central nervous system neuron differentiation / ventral midline determination / mesenchymal to epithelial transition involved in metanephric renal vesicle formation / regulation of heart morphogenesis / negative regulation of epithelial cell differentiation / Activation of SMO / alpha-tubulin acetylation / dorsal/ventral neural tube patterning / contact inhibition / negative regulation of hepatocyte proliferation / myoblast migration / epithelial-mesenchymal cell signaling / atrial septum morphogenesis / spinal cord dorsal/ventral patterning / negative regulation of DNA binding / left/right axis specification / determination of left/right asymmetry in lateral mesoderm / axon extension involved in axon guidance / midgut development / positive regulation of hepatic stellate cell activation / cell development / Hedgehog 'on' state / mammary gland epithelial cell differentiation / CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / Rap1 signalling / type B pancreatic cell development / Ion homeostasis / somite development / positive regulation of multicellular organism growth / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Factors involved in megakaryocyte development and platelet production / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / AURKA Activation by TPX2 / RET signaling / mesenchymal to epithelial transition / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of organ growth / dentate gyrus development / patched binding / VEGFA-VEGFR2 Pathway / smooth muscle tissue development / Regulation of PLK1 Activity at G2/M Transition / PKA activation / Hedgehog 'off' state / Hedgehog 'off' state / pattern specification process / forebrain morphogenesis / MAPK6/MAPK4 signaling / 9+0 non-motile cilium / GLI3 is processed to GLI3R by the proteasome / anterior/posterior pattern specification / cerebellar cortex morphogenesis / positive regulation of mesenchymal cell proliferation / cellular response to cholesterol / determination of left/right symmetry / positive regulation of branching involved in ureteric bud morphogenesis / thalamus development / cell fate specification / positive regulation of smoothened signaling pathway / dorsal/ventral pattern formation / oxysterol binding / neural crest cell migration / commissural neuron axon guidance / hair follicle morphogenesis / odontogenesis of dentin-containing tooth / smoothened signaling pathway / mesoderm formation / digestive tract development / homeostasis of number of cells within a tissue / positive regulation of neural precursor cell proliferation / cAMP-dependent protein kinase inhibitor activity / positive regulation of vascular associated smooth muscle cell migration / positive regulation of neuroblast proliferation / histone H1-4S35 kinase activity / cAMP-dependent protein kinase / positive regulation of triglyceride catabolic process / cAMP-dependent protein kinase activity / embryonic organ development / regulation of bicellular tight junction assembly / heart looping / cAMP-dependent protein kinase complex / negative regulation of glycolytic process through fructose-6-phosphate / multicellular organism growth / ciliary membrane / Mitochondrial protein degradation / sperm capacitation
Similarity search - Function
Smoothened, transmembrane domain / Smoothened, cysteine-rich domain / Frizzled/Smoothened, transmembrane domain / Frizzled/Smoothened family membrane region / Frizzled/Smoothened family membrane region / Frizzled/secreted frizzled-related protein / Frizzled / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain ...Smoothened, transmembrane domain / Smoothened, cysteine-rich domain / Frizzled/Smoothened, transmembrane domain / Frizzled/Smoothened family membrane region / Frizzled/Smoothened family membrane region / Frizzled/secreted frizzled-related protein / Frizzled / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain / Frizzled (fz) domain profile. / cAMP-dependent protein kinase catalytic subunit / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
cAMP-dependent protein kinase catalytic subunit alpha / Protein smoothened
Similarity search - Component
Biological speciesMus musculus (house mouse) / Bos taurus (domestic cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 8.59 Å
AuthorsLiu G / Myers BR
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Eye Institute (NIH/NEI)R01EY035377 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM133672 United States
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: Structural mechanism for noncanonical GPCR signaling in the Hedgehog pathway.
Authors: William P Steiner / Nathan Iverson / Guibing Liu / Varun Venkatakrishnan / Jian Wu / Tomasz Maciej Stepniewski / Zachary Michaelson / Jan W Bröckel / Ju-Fen Zhu / Jessica G H Bruystens / ...Authors: William P Steiner / Nathan Iverson / Guibing Liu / Varun Venkatakrishnan / Jian Wu / Tomasz Maciej Stepniewski / Zachary Michaelson / Jan W Bröckel / Ju-Fen Zhu / Jessica G H Bruystens / Annabel Lee / Isaac Nelson / Daniela Bertinetti / Corvin D Arveseth / Gerald Tan / Paul Spaltenstein / Jiewei Xu / Ruth Hüttenhain / Michael S Kay / Friedrich W Herberg / Erhu Cao / Jana Selent / Ganesh S Anand / Roland L Dunbrack / Susan S Taylor / Benjamin R Myers /
Abstract: The Hedgehog (Hh) pathway is fundamental to embryogenesis, tissue homeostasis and cancer. Hh signals are transduced through an unusual mechanism; upon agonist-induced phosphorylation, the ...The Hedgehog (Hh) pathway is fundamental to embryogenesis, tissue homeostasis and cancer. Hh signals are transduced through an unusual mechanism; upon agonist-induced phosphorylation, the noncanonical G-protein-coupled receptor (GPCR) Smoothened (SMO) binds the protein kinase A (PKA) catalytic subunit (PKA-C) and physically blocks its enzymatic activity. Here, by combining computational structural approaches with biochemical and functional studies, we show that SMO mimics strategies prevalent in canonical GPCR and PKA signaling complexes, despite little sequence or secondary-structure homology. The intrinsically disordered SMO cytoplasmic domain binds the PKA-C active site, resembling the regulatory subunit within PKA holoenzymes, while the SMO transmembrane domain binds a conserved PKA-C interaction hub. Unlike prevailing GPCR signal transduction models, phosphorylation of SMO promotes intramolecular electrostatic interactions that stabilize structural elements within its cytoplasmic domain, thereby remodeling it into a PKA-inhibiting conformation. Our work provides a structural mechanism for a central step in Hh signaling and defines a principle for disordered GPCR domains to transmit signals intracellularly.
History
DepositionSep 4, 2025-
Header (metadata) releaseApr 22, 2026-
Map releaseApr 22, 2026-
UpdateMay 27, 2026-
Current statusMay 27, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72508.png

Downloads & links

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Map

FileDownload / File: emd_72508.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
2.12 Å/pix.
x 128 pix.
= 271.36 Å		2.12 Å/pix.
x 128 pix.
= 271.36 Å		2.12 Å/pix.
x 128 pix.
= 271.36 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 2.12 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.2279602 - 0.599186
Average (Standard dev.)0.00024070073 (±0.046579488)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions128128128
Spacing128128128
CellA=B=C: 271.36 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_72508_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_72508_half_map_2.map
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Sample components

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Entire : BS3-crosslinked Smoothened/PKA-C complex

EntireName: BS3-crosslinked Smoothened/PKA-C complex
Components
  • Complex: BS3-crosslinked Smoothened/PKA-C complex
    • Protein or peptide: mouse Smoothened 64-674
    • Protein or peptide: native-source bovine PKA-C

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Supramolecule #1: BS3-crosslinked Smoothened/PKA-C complex

SupramoleculeName: BS3-crosslinked Smoothened/PKA-C complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 110 KDa

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Macromolecule #1: mouse Smoothened 64-674

MacromoleculeName: mouse Smoothened 64-674 / type: protein_or_peptide / ID: 1
Details: mouse Smoothened 64-674 with an N-terminal FLAG tag followed by a TEV cleavage site
Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDAGS ENLYFQGSGS PRLLSHCGRA AHCEPLRYNV CLGSALPYGA TTTLLAGDSD SQEEAHGKLV LWSGLRNAPR CWAVIQPLLC AVYMPKCEND RVELPSRTLC QATRGPCAIV ERERGWPDFL RCTPDHFPEG CPNEVQNIKF NSSGQCEAPL VRTDNPKSWY ...String:
DYKDDDDAGS ENLYFQGSGS PRLLSHCGRA AHCEPLRYNV CLGSALPYGA TTTLLAGDSD SQEEAHGKLV LWSGLRNAPR CWAVIQPLLC AVYMPKCEND RVELPSRTLC QATRGPCAIV ERERGWPDFL RCTPDHFPEG CPNEVQNIKF NSSGQCEAPL VRTDNPKSWY EDVEGCGIQC QNPLFTEAEH QDMHSYIAAF GAVTGLCTLF TLATFVADWR NSNRYPAVIL FYVNACFFVG SIGWLAQFMD GARREIVCRA DGTMRFGEPT SSETLSCVII FVIVYYALMA GVVWFVVLTY AWHTSFKALG TTYQPLSGKT SYFHLLTWSL PFVLTVAILA VAQVDGDSVS GICFVGYKNY RYRAGFVLAP IGLVLIVGGY FLIRGVMTLF SIKSNHPGLL SEKAASKINE TMLRLGIFGF LAFGFVLITF SCHFYDFFNQ AEWERSFRDY VLCQANVTIG LPTKKPIPDC EIKNRPSLLV EKINLFAMFG TGIAMSTWVW TKATLLIWRR TWCRLTGHSD DEPKRIKKSK MIAKAFSKRR ELLQNPGQEL SFSMHTVSHD GPVAGLAFDL NEPSADVSSA WAQHVTKMVA RRGAILPQDV SVTPVATPVP PEEQANMWLV EAEISPELEK RLG

UniProtKB: Protein smoothened

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Macromolecule #2: native-source bovine PKA-C

MacromoleculeName: native-source bovine PKA-C / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
SequenceString: GNAAAAKKGS EQESVKEFLA KAKEDFLKKW ENPAQNTAHL DQFERIKTLG TGSFGRVMLV KHMETGNHYA MKILDKQKVV KLKQIEHTLN EKRILQAVNF PFLVKLEFSF KDNSNLYMVM EYVPGGEMFS HLRRIGRFSE PHARFYAAQI VLTFEYLHSL DLIYRDLKPE ...String:
GNAAAAKKGS EQESVKEFLA KAKEDFLKKW ENPAQNTAHL DQFERIKTLG TGSFGRVMLV KHMETGNHYA MKILDKQKVV KLKQIEHTLN EKRILQAVNF PFLVKLEFSF KDNSNLYMVM EYVPGGEMFS HLRRIGRFSE PHARFYAAQI VLTFEYLHSL DLIYRDLKPE NLLIDQQGYI QVTDFGFAKR VKGRTWTLCG TPEYLAPEII LSKGYNKAVD WWALGVLIYE MAAGYPPFFA DQPIQIYEKI VSGKVRFPSH FSSDLKDLLR NLLQVDLTKR FGNLKNGVND IKNHKWFATT DWIAIYQRKV EAPFIPKFKG PGDTSNFDDY EEEEIRVSIN EKCGKEFSEF

UniProtKB: cAMP-dependent protein kinase catalytic subunit alpha

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 0.5 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: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 8.59 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 21122
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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