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- PDB-9wey: Structure of HCMV UL33 in complex with human Gs protein -

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Entry
Database: PDB / ID: 9wey
TitleStructure of HCMV UL33 in complex with human Gs protein
Components
  • G-protein coupled receptor homolog UL33,G-protein coupled receptor homolog UL33,G-protein coupled receptor homolog UL33, LgBit fusion
  • Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, HiBit fusion
  • Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
  • Nanobody35
KeywordsMEMBRANE PROTEIN / HCMV / viral protein / viral-host interaction / GPCR
Function / homology
Function and homology information


PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / intracellular transport / D1 dopamine receptor binding / vascular endothelial cell response to laminar fluid shear stress / activation of adenylate cyclase activity / renal water homeostasis / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway ...PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / intracellular transport / D1 dopamine receptor binding / vascular endothelial cell response to laminar fluid shear stress / activation of adenylate cyclase activity / renal water homeostasis / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of insulin secretion / cellular response to glucagon stimulus / adenylate cyclase activator activity / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / bone development / platelet aggregation / cognition / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / sensory perception of smell / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / sensory perception of taste / positive regulation of cold-induced thermogenesis / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / retina development in camera-type eye / G protein activity / GTPase binding / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / GTP binding / protein-containing complex binding / signal transduction / extracellular exosome / metal ion binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
G-protein alpha subunit, group S / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily ...G-protein alpha subunit, group S / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
Human betaherpesvirus 5
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsTsutsumi, N. / Suzuki, S. / Nishikawa, K. / Fujiyoshi, Y.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)24K01965 Japan
CitationJournal: Commun Biol / Year: 2026
Title: Activation of cytomegalovirus-encoded G protein-coupled receptor UL33 by an innate N-terminal peptide.
Authors: Anna K Drzazga / Shota Suzuki / Caroline Wouters / Felix Faas / Kouki Nishikawa / Akiko Kamegawa / Yoshinori Fujiyoshi / Mette M Rosenkilde / Naotaka Tsutsumi /
Abstract: Human cytomegalovirus (HCMV) encodes the orphan G protein-coupled receptor (GPCR) UL33, which exhibits constitutive activity that disrupts host G protein signalling, facilitating efficient viral ...Human cytomegalovirus (HCMV) encodes the orphan G protein-coupled receptor (GPCR) UL33, which exhibits constitutive activity that disrupts host G protein signalling, facilitating efficient viral replication and pathogenesis. The cryo-electron microscopy (cryo-EM) structure of UL33 bound to the G subtype of G protein reveals the N-terminal peptide as a tethered ligand reminiscent of the protease-activated receptors and adhesion GPCRs. This self-agonism induces a non-canonical active state that facilitates promiscuous G protein coupling, a plausible viral strategy for fine-tuning host signalling. Structure-guided mutagenesis disrupting key interactions between the N-terminus and its binding pocket abolishes G protein-mediated signalling, confirming the role of the N-terminus as a self-agonist. Our findings elucidate the structural basis for this activation mechanism and highlight the strategies employed by HCMV to hijack host G protein signalling.
History
DepositionAug 20, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 25, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.0Feb 25, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.0Feb 25, 2026Data content type: Mask / Part number: 3 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Feb 25, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nanobody35
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, HiBit fusion
R: G-protein coupled receptor homolog UL33,G-protein coupled receptor homolog UL33,G-protein coupled receptor homolog UL33, LgBit fusion


Theoretical massNumber of molelcules
Total (without water)177,4965
Polymers177,4965
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7729.947 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Homo sapiens (human) / References: UniProt: P59768
#2: Antibody Nanobody35


Mass: 15969.623 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#3: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 45568.238 Da / Num. of mol.: 1
Mutation: S54N, G226A, E268A, N271K, K274D, R280K, T284D, I285T, A366S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Homo sapiens (human)
References: UniProt: P63092, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, HiBit fusion / Transducin beta chain 1


Mass: 40039.648 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Homo sapiens (human) / References: UniProt: P62873
#5: Protein G-protein coupled receptor homolog UL33,G-protein coupled receptor homolog UL33,G-protein coupled receptor homolog UL33, LgBit fusion


Mass: 68188.695 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: G-protein coupled receptor homolog UL33, LgBit fusion,G-protein coupled receptor homolog UL33, LgBit fusion,G-protein coupled receptor homolog UL33, LgBit fusion,G-protein coupled receptor ...Details: G-protein coupled receptor homolog UL33, LgBit fusion,G-protein coupled receptor homolog UL33, LgBit fusion,G-protein coupled receptor homolog UL33, LgBit fusion,G-protein coupled receptor homolog UL33, LgBit fusion
Source: (gene. exp.) Human betaherpesvirus 5 / Gene: UL33 / Production host: Human betaherpesvirus 5
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: UL33-Gas-Gb1-Gg2-Nb35 / Type: COMPLEX
Details: Cytomegalovirus GPCR UL33 complexed with heterotrimeric Gs protein with dominant negative mutations via HiBit tethering stabilized by nanobody35
Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.18 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.2
Buffer component
IDConc.NameBuffer-ID
110 mMHepes-Na1
2150 mMNaCl1
30.001 % (w/v)LMNG1
40.001 % (w/v)GDN1
50.0001 % (w/v)CHS1
SpecimenConc.: 9 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 300
Details: The microscope model is the JEOL's "JEM-Z320FHC", a custom-built model of JEOL CRYO ARM 300.
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Calibrated magnification: 63291 X / Nominal defocus max: 1200 nm / Nominal defocus min: 600 nm / Cs: 3.4 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2
EM imaging opticsEnergyfilter name: In-column Omega Filter / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6particle selection
2SerialEMimage acquisition
4cryoSPARC4.6CTF correction
7Coot0.9.8.96 ELmodel fitting
9cryoSPARC4.6initial Euler assignment
10cryoSPARC4.6final Euler assignment
11cryoSPARC4.6classification
12cryoSPARC4.63D reconstruction
13PHENIX1.21.1_5286model refinement
CTF correctionDetails: CryoSPARC patch CTF estimation and global/local CTF refinements
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1502019 / Details: initial particles that appeared to be protein
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 54507 / Algorithm: FOURIER SPACE / Details: CryoSPARC non-uniform refinement / Symmetry type: POINT
Atomic model buildingB value: 106.4 / Protocol: FLEXIBLE FIT / Space: REAL
Atomic model building

3D fitting-ID: 1

IDPDB-IDAccession codeDetailsInitial refinement model-IDSource nameType
17XT8

7xt8

7XT8Gs-Nb351PDBexperimental model
2ColabFoldUL332Otherin silico model
RefinementHighest resolution: 3.3 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038264
ELECTRON MICROSCOPYf_angle_d0.60811224
ELECTRON MICROSCOPYf_dihedral_angle_d41.161133
ELECTRON MICROSCOPYf_chiral_restr0.0441302
ELECTRON MICROSCOPYf_plane_restr0.0051419

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