A glycoprotein B-neutralizing antibody structure at 2.8 Å uncovers a critical domain for herpesvirus fusion initiation

Oliver, Stefan L.; Xing, Yi; Chen, Dong-Hua; Roh, Soung Hun; Pintilie, Grigore D.; Bushnell, David A.; Sommer, Marvin H.; Yang, Edward; Carfi, Andrea; Chiu, Wah; Arvin, Ann M.

doi:10.1038/s41467-020-17911-0

Title: A glycoprotein B-neutralizing antibody structure at 2.8 Å uncovers a critical domain for herpesvirus fusion initiation

Journal Article · Tue Aug 18 00:00:00 EDT 2020 · Nature Communications

DOI:https://doi.org/10.1038/s41467-020-17911-0· OSTI ID:1650354

^[1]; Xing, Yi ^[2];

^[1]; Roh, Soung Hun ^[3]; Pintilie, Grigore D. ^[1];

^[1]; Sommer, Marvin H. ^[1]; Yang, Edward ^[1]; Carfi, Andrea ^[2];

^[4];

^[1]

Stanford Univ., CA (United States). School of Medicine
GSK Vaccines, Cambridge, MA (United States); SLAC National Accelerator Lab., Menlo Park, CA (United States)
Seoul National Univ. (Korea, Republic of)
Stanford Univ., CA (United States). School of Medicine; SLAC National Accelerator Lab., Menlo Park, CA (United States)

Members of the Herpesviridae, including the medically important alphaherpesvirus varicella-zoster virus (VZV), induce fusion of the virion envelope with cell membranes during entry, and between cells to form polykaryocytes in infected tissues. The conserved glycoproteins, gB, gH and gL, are the core functional proteins of the herpesvirus fusion complex. gB serves as the primary fusogen via its fusion loops, but functions for the remaining gB domains remain unexplained. As a pathway for biological discovery of domain function, our approach used structure-based analysis of the viral fusogen together with a neutralizing antibody. We report here a 2.8 Å cryogenic-electron microscopy structure of native gB recovered from VZV-infected cells, in complex with a human monoclonal antibody, 93k. This high-resolution structure guided targeted mutagenesis at the gB-93k interface, providing compelling evidence that a domain spatially distant from the gB fusion loops is critical for herpesvirus fusion, revealing a potential new target for antiviral therapies. Herpesvirus virions have an outer lipid membrane dotted with glycoproteins that enable fusion with cell membranes to initiate entry and establish infection. Here the authors elucidate the structural mechanism of a neutralizing antibody derived from a patient infected by the herpesvirus varicella-zoster virus and targeted to its fusogen, glycoprotein-B.

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Research Organization:: SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH)

Grant/Contract Number:: P41-GM103832; R01-AI102546; R01-GM079429; R37-AI20459; S10-OD021600

OSTI ID:: 1650354

Journal Information:: Nature Communications, Vol. 11, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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