Exploring the conformational dynamics of PD1 in complex with different ligands: What we can learn for designing novel...

Area of Science:

• Immunology
• Molecular Biology
• Computational Biology

Background:

• T cell activation leads to programmed cell death 1 (PD1) expression.
• PD1 engagement with ligands PDL1/PDL2 inhibits T cell proliferation and effector functions.
• The precise mechanism of PD1 ligand binding-induced T cell inhibition remains unclear.

Purpose of the Study:

• Investigate the dynamics of PD1 in its free state and bound to PDL1 variants and therapeutic antibodies.
• Assess conformational changes in PD1 associated with signaling.
• Elucidate how ligand binding influences PD1-mediated T cell inhibition.

Main Methods:

• Molecular dynamics simulations were employed.
• Analyzed PD1 conformational dynamics.
• Examined interactions with PDL1 variants, nivolumab, and pembrolizumab.

Main Results:

• PDL1 variants bind to PD1 via a pre-conformational selection mechanism.
• Therapeutic antibodies like nivolumab and pembrolizumab utilize an induced-fit model for PD1 binding.
• The extent of conformational change in PD1's C'D loop correlates with the ligand's ability to reduce inhibitory signaling.

Conclusions:

• Ligand-induced conformational changes in the PD1 C'D loop are critical for modulating T cell inhibition.
• Targeting specific PD1 loop conformations presents a potential therapeutic avenue for enhancing T cell effector functions.
• Understanding these dynamics can inform the design of novel immunotherapies.