Redesigning HVEM Interface for Selective Binding to LIGHT, BTLA, and CD160.
Structure
; 28(11): 1197-1205.e2, 2020 11 03.
Article
em En
| MEDLINE
| ID: mdl-32795404
ABSTRACT
Herpes virus entry mediator (HVEM) regulates positive and negative signals for T cell activation through co-signaling pathways. Dysfunction of the HVEM co-signaling network is associated with multiple pathologies related to autoimmunity, infectious disease, and cancer, making the associated molecules biologically and therapeutically attractive targets. HVEM interacts with three ligands from two different superfamilies using two different binding interfaces. The engagement with ligands CD160 and B- and T-lymphocyte attenuator (BTLA), members of immunoglobulin superfamily, is associated with inhibitory signals, whereas inflammatory responses are regulated through the interaction with LIGHT from the TNF superfamily. We computationally redesigned the HVEM recognition interfaces using a residue-specific pharmacophore approach, ProtLID, to achieve switchable-binding specificity. In subsequent cell-based binding assays the new interfaces, designed with only single or double mutations, exhibited selective binding to only one or two out of the three cognate ligands.
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MEDLINE
Assunto principal:
Receptores Virais
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Receptores Imunológicos
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Antígenos CD
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Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral
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Membro 14 de Receptores do Fator de Necrose Tumoral
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article