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TitleStructural basis for HCMV Pentamer receptor recognition and antibody neutralization.
Journal, issue, pagesSci Adv, Vol. 8, Issue 10, Page eabm2536, Year 2022
Publish dateMar 11, 2022
AuthorsMarc 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 /
PubMed AbstractHuman 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 ...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.
External linksSci Adv / PubMed:35275719 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.84 Å
Structure data

25685

7t4q

EMDB-25685, PDB-7t4q:
CryoEM structure of the HCMV Pentamer gH/gL/UL128/UL130/UL131A in complex with neutralizing fabs 2C12, 7I13 and 13H11
Method: EM (single particle) / Resolution: 2.9 Å

25686

7t4r

EMDB-25686, PDB-7t4r:
CryoEM structure of the HCMV Pentamer gH/gL/UL128/UL130/UL131A in complex with THBD and neutralizing fabs MSL-109 and 13H11
Method: EM (single particle) / Resolution: 3.3 Å

25687

7t4s

EMDB-25687, PDB-7t4s:
CryoEM structure of the HCMV Pentamer gH/gL/UL128/UL130/UL131A in complex with NRP2 and neutralizing fabs 8I21 and 13H11
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-25688: CryoEM structure of 2x HCMV Pentamer gH/gL/UL128/UL130/UL131A in complex with NRP2 and 2x neutralizing fabs 8I21 and 13H11
Method: EM (single particle) / Resolution: 3.84 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-CA:
Unknown entry

Source
  • human betaherpesvirus 5
  • homo sapiens (human)
KeywordsVIRAL PROTEIN/Immune System / Human Cytomegalovirus / glycoprotein complex / antibody complex / VIRAL PROTEIN / VIRAL PROTEIN-Immune System complex / thrombomodulin / Neuropilin 2

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