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

Human cytomegalovirus (HCMV) encodes G protein-coupled receptors (GPCRs) and , 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, e...

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Bibliographic Details
Published in:Science advances 2022-01, Vol.8 (3), p.eabl5442-eabl5442
Main Authors: Tsutsumi, Naotaka, Maeda, Shoji, Qu, Qianhui, Vögele, Martin, Jude, Kevin M, Suomivuori, Carl-Mikael, Panova, Ouliana, Waghray, Deepa, Kato, Hideaki E, Velasco, Andrew, Dror, Ron O, Skiniotis, Georgios, Kobilka, Brian K, Garcia, K Christopher
Format: Article
Language:English
Subjects:
Animals
Biomedicine and Life Sciences
Cryoelectron Microscopy
Cytomegalovirus - metabolism
GTP-Binding Proteins - metabolism
Health and Medicine
Humans
Mammals - metabolism
Receptors, Chemokine - metabolism
SciAdv r-articles
Structural Biology
Viral Proteins - chemistry
Virology
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Summary:Human cytomegalovirus (HCMV) encodes G protein-coupled receptors (GPCRs) and , 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abl5442