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

Roberta Pascolutti, Xianqiang Sun, Joseph Kao, Roy L. Maute, Aaron M. Ring, Gregory R. Bowman, Andrew C. Kruse

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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.

Original languageEnglish
Pages (from-to)1719-1728
Number of pages10
JournalStructure
Volume24
Issue number10
DOIs
StatePublished - Oct 4 2016

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