Human PD-1 binds differently to its human ligands: A comprehensive modeling study

摘要: Programmed death-1 (PD-1) is a potent inhibitory receptor of T cells which binds to two different ligands, namely PD-L1 and PD-L2, upon binding, it inhibits cell activation, differentiation, proliferation, leading state immune tolerance. Blocking these interactions recently emerged as 'game changer' approach in immunotherapy. Despite the significant therapeutic potential targeting PD-1 pathway, interaction between human its ligands not fully understood. Current crystal structures describe mouse with or PD-L2. However, recent mutational nuclear magnetic resonance (NMR) analyses suggest that differently compared their counterparts. No detailed model currently available consistently fit data. The lack accurate constitutes high barrier against rationally developing more effective safer agents interactions. Here we for first time models bound ligands. Our methodology involved combining molecular dynamics (MD) simulations protein-protein docking binding energy analysis predict most probable conformations PD1 results confirm experimental NMR data reveal atomistic details so far how PD-Ls why bind affinities same receptor.