Predicting a Stable Dimeric Form of the PD1-PDL1 Complex: Implications for Understanding the PD1 Activation Mechanism

J Phys Chem B. 2023 Jul 6;127(26):5764-5771. doi: 10.1021/acs.jpcb.3c00911. Epub 2023 Jun 21.

Abstract

The activation of T cells is typically accompanied by inhibitory mechanisms within which the programmed cell death (PD1) receptor stands out. Upon binding the ligands PDL1 and PDL2, PD1 drives T cells to an unresponsive state called exhaustion, characterized by a markedly decreased capacity to exert effector functions. 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 is activated upon the ligands' binding remains an open question. Several experimental facts suggest that the activation of the PD1-PLD1 pathway depends on the interaction with an unknown partner at the cellular membrane. In this work, we investigate the possibility that the target of PD1-PDL1 is the same PD1-PDL1 complex. We combined molecular docking with molecular dynamics and umbrella sampling simulations to explore different binding modes and assess the complexes' stability. We predicted a stable dimeric form of the extracellular domains of the PD1-PDL1 complex. This dimeric complex has an affinity comparable to the PD1-PDL1 interaction and resembles the form of a linear lattice. We proposed a new model for PD1 activation where the PD1-PDL1 dimeric form could facilitate the interaction of the intracellular domains of PD1 and the further binding and activation of the SHP2 phosphatase. This model might explain the inhibitory effect of anti-PD1/PDL1 antibodies through the prevention of the formation of the PD1-PDL1 dimers and, subsequently, the abrogation of the SHP2 phosphatase activation.

MeSH terms

  • Ligands
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11*

Substances

  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ligands