Structural basis for HCMV Pentamer receptor recognition and antibody neutralization

HCMV 五聚体受体识别和抗体中和的结构基础

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作者:Marc Kschonsak, Matthew C Johnson, Rachel Schelling, Evan M Green, Lionel Rougé, Hoangdung Ho, Nidhi Patel, Cem Kilic, Edward Kraft, Christopher P Arthur, Alexis L Rohou, Laetitia Comps-Agrar, Nadia Martinez-Martin, Laurent Perez, Jian Payandeh, Claudio Ciferri

Abstract

Human cytomegalovirus (HCMV) represents the viral leading cause of congenital birth defects and uses the gH/gL/UL128-130-131A complex (Pentamer) to enter different cell types, including epithelial and endothelial cells. Upon infection, Pentamer elicits the most potent neutralizing response against HCMV, representing a key vaccine candidate. Despite its relevance, the structural basis for Pentamer receptor recognition and antibody neutralization is largely unknown. Here, we determine the structures of Pentamer bound to neuropilin 2 (NRP2) and a set of potent neutralizing antibodies against HCMV. Moreover, we identify thrombomodulin (THBD) as a functional HCMV receptor and determine the structures of the Pentamer-THBD complex. Unexpectedly, both NRP2 and THBD also promote dimerization of Pentamer. Our results provide a framework for understanding HCMV receptor engagement, cell entry, antibody neutralization, and outline strategies for antiviral therapies against HCMV.

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