Unraveling a Conserved Conformation of the FG Loop upon the Binding of Natural Ligands to the Human and Murine PD1.

The activation of T cells is normally accompanied by inhibitory mechanisms within which the PD1 receptor stands out. PD1 drives T cells to an unresponsive state called exhaustion, characterized by a markedly decreased capacity to exert effector functions upon binding the ligands PDL1 and PDL2. For this reason, PD1 has become one of the most important targets in cancer immunotherapy. Despite the numerous studies about PD1 signaling modulation, how the PD1 signaling pathway is activated upon the ligands' binding remains an open question. In this work, we used molecular dynamics simulations to assess the differences of the PD1 motion in the free state and in complex with the ligands. We found that, in both human and murine systems, the binding of PDL1 and PDL2 stabilizes the conformation of the FG loop similarly. This result, combined with the conservation of the FG loop residues across species, suggests that the conformation of the FG loop is somehow related to the signaling process. We also found a high similarity between the PD1-PDL1 structures with the variable region of an antibody structure, where the FG loop occupies a similar position to the CDR3 light chain.