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

Sci Adv. 2022 Jan 21;8(3):eabl5442. doi: 10.1126/sciadv.abl5442. Epub 2022 Jan 21.

Abstract

Human cytomegalovirus (HCMV) encodes G protein-coupled receptors (GPCRs) US28 and US27, which facilitate viral pathogenesis through engagement of host G proteins. Here we report cryo-electron microscopy structures of US28 and US27 forming nonproductive and productive complexes with Gi and Gq, respectively, exhibiting unusual features with functional implications. The "orphan" GPCR US27 lacks a ligand-binding pocket and has captured a guanosine diphosphate-bound inactive Gi through a tenuous interaction. The docking modes of CX3CL1-US28 and US27 to Gi favor localization to endosome-like curved membranes, where US28 and US27 can function as nonproductive Gi sinks to attenuate host chemokine-dependent Gi signaling. The CX3CL1-US28-Gq/11 complex likely represents a trapped intermediate during productive signaling, providing a view of a transition state in GPCR-G protein coupling for signaling. Our collective results shed new insight into unique G protein-mediated HCMV GPCR structural mechanisms, compared to mammalian GPCR counterparts, for subversion of host immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cryoelectron Microscopy
  • Cytomegalovirus* / metabolism
  • GTP-Binding Proteins / metabolism
  • Humans
  • Mammals / metabolism
  • Receptors, Chemokine* / metabolism
  • Viral Proteins / chemistry

Substances

  • Receptors, Chemokine
  • Viral Proteins
  • GTP-Binding Proteins