Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant.

Publication Type:

Journal Article


Structure, Volume 24, Issue 10, p.1719-1728 (2016)


Antigens, CD274, Binding Sites, Crystallography, X-Ray, Humans, Hydrogen-Ion Concentration, Models, Molecular, Molecular Dynamics Simulation, Point Mutation, Programmed Cell Death 1 Receptor, Protein Binding, Protein Structure, Secondary


<p>The immune checkpoint receptor PD-1 and its ligand, PD-L1, have emerged as key regulators of anti-tumor immunity in humans. Recently, we reported an ultra-high-affinity PD-1 mutant, termed high-affinity consensus (HAC) PD-1, which shows superior therapeutic efficacy in mice compared with antibodies. However, the molecular details underlying the action of this agent remain incompletely understood, and a molecular view of PD-1/PD-L1 interactions in general is only beginning to emerge. Here, we report the structure of HAC PD-1 in complex with PD-L1, showing that it binds PD-L1 using a unique set of polar interactions. Biophysical studies and long-timescale molecular dynamics experiments reveal the mechanisms by which ten point mutations confer a 35,000-fold enhancement in binding affinity, and offer atomic-scale views of the role of conformational dynamics in PD-1/PD-L1 interactions. Finally, we show that the HAC PD-1 exhibits pH-dependent affinity, with pseudo-irreversible binding in a low pH setting akin to the tumor microenvironment.</p>