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Cell ; 184(5): 1232-1244.e16, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33626330

RESUMO

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 (TGFßR3) 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 TGFßR3 as well as two broadly neutralizing antibodies. Trimer binding to PDGFRα and TGFßR3 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.


Assuntos
Citomegalovirus/química , Glicoproteínas de Membrana/química , Proteínas do Envelope Viral/química , Internalização do Vírus , Microscopia Crioeletrônica , Citomegalovirus/fisiologia , Glicoproteínas de Membrana/metabolismo , Modelos Moleculares , Proteoglicanas/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/química , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteínas do Envelope Viral/metabolismo
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