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- EMDB-74331: SMO/PKA-C complex in MSP1E3D1 nanodiscs -

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Basic information

Entry
Database: EMDB / ID: EMD-74331
TitleSMO/PKA-C complex in MSP1E3D1 nanodiscs
Map data
Sample
  • Complex: SMO/PKA-C
    • Protein or peptide: mouse Smoothened 64-674
    • Protein or peptide: native-source bovine PKA-C
KeywordsHedgehog signaling / SIGNALING PROTEIN
Biological speciesMus musculus (house mouse) / Bos taurus (domestic cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 8.57 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
DepositionDec 5, 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_74331.png

Downloads & links

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Map

FileDownload / File: emd_74331.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
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.22739807 - 0.5670216
Average (Standard dev.)-0.0007162786 (±0.043485574)
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_74331_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_74331_half_map_2.map
Projections & Slices
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Sample components

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Entire : SMO/PKA-C

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

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Supramolecule #1: SMO/PKA-C

SupramoleculeName: SMO/PKA-C / 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: FLAG-tagged mouse Smoothened 64-674 / 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

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Macromolecule #2: native-source bovine PKA-C

MacromoleculeName: native-source bovine PKA-C / type: protein_or_peptide / ID: 2 / Details: native PKA-C purified from beef heart / 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

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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: 3.5 µm / Nominal defocus min: 1.0 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: 8.57 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 43052
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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