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

Area of Science:

• Immunology
• Molecular Biology
• Computational Biology

Background:

• Programmed cell death protein 1 (PD1) is a key inhibitory receptor on T cells, inducing exhaustion and limiting anti-tumor immunity.
• PD1 signaling, triggered by its ligands PDL1 and PDL2, is a major target in cancer immunotherapy, but its precise activation mechanism remains unclear.
• Existing research suggests an unknown membrane partner mediates PD1-PDL1 pathway activation.

Purpose of the Study:

• To investigate the hypothesis that the PD1-PDL1 complex itself acts as the activating partner.
• To elucidate the structural basis of PD1-PDL1 complex formation and its role in signal transduction.
• To propose a novel model for PD1 receptor activation and its inhibition by therapeutic antibodies.

Main Methods:

• Utilized molecular docking to predict potential binding modes of the PD1-PDL1 complex.
• Employed molecular dynamics and umbrella sampling simulations to assess complex stability and binding affinities.
• Analyzed the structural characteristics of predicted PD1-PDL1 complexes.

Main Results:

• Predicted a stable dimeric form of the extracellular domains of the PD1-PDL1 complex.
• The dimeric complex exhibits comparable binding affinity to the monomeric PD1-PDL1 interaction and forms a linear lattice-like structure.
• This dimeric conformation is proposed to facilitate intracellular PD1 domain interactions and subsequent SHP2 phosphatase binding and activation.

Conclusions:

• The PD1-PDL1 complex can form a stable dimer, providing a potential mechanism for PD1 receptor activation.
• This dimeric model offers a new explanation for how PD1 signaling leads to T cell exhaustion via SHP2 phosphatase.
• The findings suggest that anti-PD1/PDL1 antibodies may exert their inhibitory effects by disrupting PD1-PDL1 dimer formation, thereby blocking SHP2 activation.