9WEY

Structure of HCMV UL33 in complex with human Gs protein

Summary for 9WEY

• Entry DOI: 10.2210/pdb9wey/pdb
• EMDB information: 65918
• Descriptor: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Nanobody35, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (5 entities in total)
• Functional Keywords: hcmv, viral protein, viral-host interaction, gpcr, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 177496.15

Authors

Tsutsumi, N.,Suzuki, S.,Nishikawa, K.,Fujiyoshi, Y. (deposition date: 2025-08-20, release date: 2026-02-25)

Primary citation

Drzazga, A.K.,Suzuki, S.,Wouters, C.,Faas, F.,Nishikawa, K.,Kamegawa, A.,Fujiyoshi, Y.,Rosenkilde, M.M.,Tsutsumi, N.
Activation of cytomegalovirus-encoded G protein-coupled receptor UL33 by an innate N-terminal peptide.
Commun Biol, 2026

PubMed 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 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.

PubMed: 41680497
DOI: 10.1038/s42003-026-09660-5

Experimental method

ELECTRON MICROSCOPY (3.3 Å)