2. Academic Validation
  3. Redesigning HVEM Interface for Selective Binding to LIGHT, BTLA, and CD160

Redesigning HVEM Interface for Selective Binding to LIGHT, BTLA, and CD160

  • Structure. 2020 Nov 3;28(11):1197-1205.e2. doi: 10.1016/j.str.2020.07.013.
Rojan Shrestha 1,  Sarah C Garrett-Thomson 2,  Weifeng Liu 2,  Steven C Almo 3,  Andras Fiser 4
Affiliations

Affiliations

  • 1 Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
  • 2 Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
  • 3 Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Electronic address: steve.almo@einsteinmed.org.
  • 4 Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Electronic address: andras.fiser@einsteinmed.org.
PMID: 32795404 DOI: 10.1016/j.str.2020.07.013
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.

Keywords

HVEM; ProtLID; computational interface design; immune synapse; protein-based drug discovery; protein-protein interactions; residue-specific pharmacophores; switchable-binding selectivity.

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