@article {889726,
	title = {Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant},
	journal = {Structure},
	volume = {24},
	number = {10},
	year = {2016},
	month = {2016 Oct 04},
	pages = {1719-1728},
	abstract = {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.},
	keywords = {B7-H1 Antigen, 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},
	issn = {1878-4186},
	doi = {10.1016/j.str.2016.06.026},
	author = {Pascolutti, Roberta and Sun, Xianqiang and Kao, Joseph and Maute, Roy L and Ring, Aaron M and Bowman, Gregory R and Kruse, Andrew C}
}
