Computer-aided design of PVR mutants with enhanced binding affinity to TIGIT

Area of Science:

• Immunology
• Structural Biology
• Computational Chemistry

Background:

• TIGIT (T cell immunoglobulin and ITIM domain) is an immune checkpoint molecule that binds PVR (poliovirus receptor) to induce immune tolerance.
• Blocking the TIGIT/PVR pathway is a potential strategy for cancer immunotherapy.
• Understanding the structural basis of TIGIT/PVR interaction is crucial for designing effective inhibitors.

Purpose of the Study:

• To investigate the structural characteristics and binding mechanism of the TIGIT/PVR interaction.
• To identify PVR mutants with enhanced affinity to TIGIT for potential therapeutic applications.

Main Methods:

• Molecular dynamics (MD) simulations were employed to analyze the TIGIT/PVR interaction.
• In silico mutagenesis was used to design PVR mutants.
• Biological activity of PVR mutants was evaluated using TIGIT-overexpressed Jurkat cells.

Main Results:

• MD simulations revealed significant intra-molecular rearrangements in PVR loops and increased hydrogen bonding with TIGIT.
• Key residues involved in PVR-TIGIT interaction were identified.
• Four PVR mutants (S72W, S72R, G131V, S132Q) demonstrated enhanced affinity to TIGIT and stronger inhibitory effects than wild-type PVR.

Conclusions:

• MD simulations provide novel insights into the TIGIT/PVR binding model.
• The identified PVR mutants represent promising candidates for developing novel immunotherapies targeting the TIGIT/PVR pathway.
• These mutants could enhance anti-cancer immune responses by blocking TIGIT-mediated immune suppression.