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Structure paper

TitleStructures of HCMV Trimer reveal the basis for receptor recognition and cell entry.
Journal, issue, pagesCell, Vol. 184, Issue 5, Page 1232-1244.e16, Year 2021
Publish dateMar 4, 2021
AuthorsMarc Kschonsak / Lionel Rougé / Christopher P Arthur / Ho Hoangdung / Nidhi Patel / Ingrid Kim / Matthew C Johnson / Edward Kraft / Alexis L Rohou / Avinash Gill / Nadia Martinez-Martin / Jian Payandeh / Claudio Ciferri /
PubMed AbstractHuman cytomegalovirus (HCMV) infects the majority of the human population and represents the leading viral cause of congenital birth defects. HCMV utilizes the glycoproteins gHgLgO (Trimer) to bind ...Human cytomegalovirus (HCMV) infects the majority of the human population and represents the leading viral cause of congenital birth defects. HCMV utilizes the glycoproteins gHgLgO (Trimer) to bind to platelet-derived growth factor receptor alpha (PDGFRα) and transforming growth factor beta receptor 3 (TGFβR3) to gain entry into multiple cell types. This complex is targeted by potent neutralizing antibodies and represents an important candidate for therapeutics against HCMV. Here, we determine three cryogenic electron microscopy (cryo-EM) structures of the trimer and the details of its interactions with four binding partners: the receptor proteins PDGFRα and TGFβR3 as well as two broadly neutralizing antibodies. Trimer binding to PDGFRα and TGFβR3 is mutually exclusive, suggesting that they function as independent entry receptors. In addition, Trimer-PDGFRα interaction has an inhibitory effect on PDGFRα signaling. Our results provide a framework for understanding HCMV receptor engagement, neutralization, and the development of anti-viral strategies against HCMV.
External linksCell / PubMed:33626330
MethodsEM (single particle)
Resolution2.6 - 2.9 Å
Structure data

EMDB-23252, PDB-7lbe:
CryoEM structure of the HCMV Trimer gHgLgO in complex with neutralizing fabs 13H11 and MSL-109
Method: EM (single particle) / Resolution: 2.9 Å

EMDB-23253, PDB-7lbf:
CryoEM structure of the HCMV Trimer gHgLgO in complex with human Platelet-derived growth factor receptor alpha and neutralizing fabs 13H11 and MSL-109
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-23254, PDB-7lbg:
CryoEM structure of the HCMV Trimer gHgLgO in complex with human Transforming growth factor beta receptor type 3 and neutralizing fabs 13H11 and MSL-109
Method: EM (single particle) / Resolution: 2.6 Å

Chemicals

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

ChemComp-MAN:
alpha-D-mannopyranose / Mannose

Source
  • human cytomegalovirus
  • homo sapiens (human)
  • human cytomegalovirus (strain merlin)
  • Human cytomegalovirus HHV-5
KeywordsVIRAL PROTEIN/Immune System / virus / receptor / complex / neutralizing antibody / VIRAL PROTEIN / VIRAL PROTEIN-Immune System complex

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