Traversing through the Dynamic Protein-Protein InteractionLandscape and Conformational Plasticity of PD-1 for Small-MoleculeDiscovery

摘要

Monoclonal antibodies (mAbs) blocking the PD-1/PD-L1interface have shown remarkable success in treating malignancies, but theymay also initiate lethal immune-related adverse events. Small moleculesmay circumvent the mAb limitations; however, none has entered clinicaltrials targeting PD-1. Its complex protein-protein interaction interfacesnecessitate an atomic-level understanding of recognition and bindingmechanisms. Hence, we have aimed to highlight the PD-1's sequence-structure-dynamic-function link with its cognate ligands and diverselyreported inhibitors. We focus primarily on the anti-PD-1 mAbs, theirmode of actions, and interactions with PD-1 epitopes. The comparison ofco-crystals showed that these ligands/inhibitors harness the PD-1'sconformational plasticity and structural determinants differentially. Therelationship between modulator binding patterns and biological activity isdemonstrated using interactionfingerprinting of all reported human PD-1co-crystals. The significant dynamical events and hot-spot residues underpinned from crystallographic wealth and computationalstudies have been highlighted to expedite small-molecule discovery.