Related Experiment Video

Updated: Oct 5, 2025

Strategic Screening and Characterization of the Visual GPCR-mini-G Protein Signaling Complex for Successful Crystallization
09:19

Strategic Screening and Characterization of the Visual GPCR-mini-G Protein Signaling Complex for Successful Crystallization

Published on: March 16, 2020

7.1K

Atypical structural snapshots of human cytomegalovirus GPCR interactions with host G proteins

Naotaka Tsutsumi1,2,3, Shoji Maeda1, Qianhui Qu1,2

  • 1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.

Science Advances
|January 21, 2022
PubMed

Insights

Human cytomegalovirus (HCMV) G protein-coupled receptors US28 and US27 bind host G proteins in unique ways. Structural insights reveal how these viral GPCRs subvert host immunity, offering new therapeutic targets.

Area of Science:

  • Structural biology
  • Virology
  • Immunology

Background:

  • Human cytomegalovirus (HCMV) utilizes viral G protein-coupled receptors (GPCRs), US28 and US27, for pathogenesis.
  • These viral GPCRs interact with host G proteins to modulate cellular functions.

Purpose of the Study:

  • To elucidate the structural mechanisms of HCMV US28 and US27 in complex with host Gi and Gq proteins.
  • To understand how these viral GPCRs differ from mammalian GPCRs in G protein coupling and signaling.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine high-resolution structures.
  • Complexes of US28 and US27 with Gi and Gq proteins, including ligand-bound states, were analyzed.

Main Results:

  • Structures revealed nonproductive and productive complexes of US28/US27 with Gi and Gq.
  • US27, an orphan GPCR, binds inactive Gi without a canonical ligand-binding pocket.
  • Docking modes suggest localization to endosomal membranes, acting as Gi sinks to inhibit host signaling.
  • A CX3CL1-US28-Gq complex captured a transition state in GPCR-G protein coupling.

Conclusions:

  • HCMV GPCRs US28 and US27 exhibit unique structural features and G protein interaction modes compared to host GPCRs.
  • These viral GPCRs play a role in subverting host immunity by modulating G protein signaling pathways.
  • The findings provide structural insights into HCMV pathogenesis and potential therapeutic strategies.

More Related Videos

HSV-Mediated Transgene Expression of Chimeric Constructs to Study Behavioral Function of GPCR Heteromers in Mice07:30

HSV-Mediated Transgene Expression of Chimeric Constructs to Study Behavioral Function of GPCR Heteromers in Mice

Published on: July 9, 2016

7.4K
A Comparative Approach to Characterize the Landscape of Host-Pathogen Protein-Protein Interactions13:56

A Comparative Approach to Characterize the Landscape of Host-Pathogen Protein-Protein Interactions

Published on: July 18, 2013

11.3K

Related Concept Videos

G Protein-coupled Receptors01:15

G Protein-coupled Receptors

G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
13.9K
Transducer Mechanism: G Protein–Coupled Receptors01:30

Transducer Mechanism: G Protein–Coupled Receptors

G Protein–Coupled Receptors (GPCRs) are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to various stimuli. GPCRs regulate critical physiological pathways and are excellent drug targets for treating diseases such as diabetes, cancer, obesity, depression, or Alzheimer's. Nearly 35% of approved drugs implement their therapeutic effects by selectively interacting with specific GPCRs.
GPCRs are also called heptahelical,...
2.8K
Activation and Inactivation of G Proteins01:22

Activation and Inactivation of G Proteins

Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
7.9K
G-protein Coupled Receptors01:21

G-protein Coupled Receptors

G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
123.3K
Assembly of Signaling Complexes01:30

Assembly of Signaling Complexes

Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
6.0K
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
6.1K