EMD-25685
CryoEM structure of the HCMV Pentamer gH/gL/UL128/UL130/UL131A in complex with neutralizing fabs 2C12, 7I13 and 13H11
EMD-25685
Single-particle2.9 Å
Deposition: 10/12/2021Map released: 23/03/2022
Last modified: 13/11/2024
Sample Organism:
Homo sapiens,
Human betaherpesvirus 5
Sample: Pentameric complex of HCMV proteins gH, gL, UL128, UL130, UL131A bound to fabs of human neutralizing antibodies 2C12, 7I13 and 13H11
Fitted models: 7t4q (Avg. Q-score: 0.54)
Deposition Authors: Kschonsak M
,
Johnson MC
Sample: Pentameric complex of HCMV proteins gH, gL, UL128, UL130, UL131A bound to fabs of human neutralizing antibodies 2C12, 7I13 and 13H11
Fitted models: 7t4q (Avg. Q-score: 0.54)
Deposition Authors: Kschonsak M
,
Johnson MC
Structural basis for HCMV Pentamer receptor recognition and antibody neutralization.
Kschonsak M ,
Johnson MC ,
Schelling R,
Green EM,
Rouge L ,
Ho H ,
Patel N ,
Kilic C,
Kraft E ,
Arthur CP ,
Rohou AL ,
Comps-Agrar L ,
Martinez-Martin N,
Perez L ,
Payandeh J ,
Ciferri C
(2022) Sci Adv , 8 , eabm2536 - eabm2536
,
Johnson MC ,
Schelling R,
Green EM,
Rouge L ,
Ho H ,
Patel N ,
Kilic C,
Kraft E ,
Arthur CP ,
Rohou AL ,
Comps-Agrar L ,
Martinez-Martin N,
Perez L ,
Payandeh J ,
Ciferri C
(2022) Sci Adv , 8 , eabm2536 - eabm2536
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.
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.