Baby Steps Toward Modelling The Full human Programmed Death-1 (PD-1) Pathway

Immune checkpoints play a vital role in regulating the immune system. They preserve the immunological balance between preventing continuous activated immune responses and defending against chronic infections and cancer. Blocking the immune inhibitory checkpoints pathways recently emerged as a ‘game changer’ approach in cancer and antiviral immunotherapy. Modeling these pathways at the atomic level provides a key step toward rationally designing selective blockers for these pathways. Current crystal structures for the immune checkpoints are mainly not for human and are very limited in their scope of interactions. Our team has been focused on building atomistic models for these proteins, characterizing their protein-protein interactions and designing new inhibitory drugs for their activity. This article highlights our recent study on modelling the human Programmed Death-1 (hPD-1) pathway by characterizing the interactions between hPD-1 and its two human ligands. In this study, we showed that hPD1 binds differently to its two ligands. We also showed that the modes of binding for each ligand are different between mouse and human, emphasizing the limited information in current mouse crystal structures. Our findings enhanced the understanding of the receptor-ligand(s) interactions and formed a significant step toward building a full model for the whole PD1 pathway. This undoubtedly will foster the ongoing efforts to develop antibodies and small molecule drugs against this important T cell immune-regulatory mechanism.