Related Experiment Video

Updated: Feb 14, 2026

Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
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Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors

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Activation of cytomegalovirus-encoded G protein-coupled receptor UL33 by an innate N-terminal peptide

Anna K Drzazga1, Shota Suzuki2, Caroline Wouters1,3

  • 1Department of Biomedical Sciences, Laboratory for Molecular and Translational Pharmacology, University of Copenhagen, Copenhagen, Denmark.

Communications Biology
|February 12, 2026
PubMed

Insights

Human cytomegalovirus (HCMV) uses its UL33 G protein-coupled receptor (GPCR) to disrupt host signaling. The UL33 N-terminus acts as a self-agonist, enabling viral replication and pathogenesis.

Area of Science:

  • Virology
  • Structural Biology
  • Molecular Biology

Background:

  • Human cytomegalovirus (HCMV) encodes the orphan G protein-coupled receptor (GPCR) UL33.
  • UL33 exhibits constitutive activity, disrupting host G protein signaling and aiding viral replication and pathogenesis.

Purpose of the Study:

  • To elucidate the structural basis of UL33's activation mechanism.
  • To understand how HCMV hijacks host G protein signaling.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine the structure of UL33 bound to Gs.
  • Structure-guided mutagenesis to investigate the role of the N-terminus.

Main Results:

  • The cryo-EM structure revealed UL33's N-terminal peptide as a tethered ligand, inducing a self-agonistic, non-canonical active state.
  • This active state facilitates promiscuous G protein coupling, a strategy for fine-tuning host signaling.
  • Mutagenesis confirmed the N-terminus's role as a self-agonist by abolishing G protein signaling.

Conclusions:

  • The N-terminus of HCMV's UL33 receptor acts as an intrinsic self-agonist.
  • This mechanism allows HCMV to effectively manipulate host G protein signaling pathways for viral advantage.

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