TY - JOUR
T1 - Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant
AU - Pascolutti, Roberta
AU - Sun, Xianqiang
AU - Kao, Joseph
AU - Maute, Roy L.
AU - Ring, Aaron M.
AU - Bowman, Gregory R.
AU - Kruse, Andrew C.
N1 - Funding Information:
G.R.B. holds a Career Award at the Scientific Interface from the Burroughs Welcome Fund. We gratefully acknowledge the support of NVIDIA Corporation with the donation of the GTX Titan X GPU used for our simulations. X-ray crystallographic data were collected at NE-CAT beamline 24ID-C. We would like also to recognize Dr. K. Arnett for assistance in SEC-MALS data collection and analysis and Dr. B. Zimmerman for helpful experimental discussion. This work was supported in part by NIH grant 1DP5OD021345 to A.C.K. The authors J.K. and R.L.M. are paid employees of Ab Initio Biotherapeutics, Inc., which holds the license to a patent on the HAC PD-1 mutant. R.L.M., A.M.R., and A.C.K. are founders of Ab Initio Biotherapeutics, and A.M.R and A.C.K. are members of the Scientific Advisory Board.
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/10/4
Y1 - 2016/10/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84989835479&partnerID=8YFLogxK
U2 - 10.1016/j.str.2016.06.026
DO - 10.1016/j.str.2016.06.026
M3 - Article
C2 - 27618663
AN - SCOPUS:84989835479
SN - 0969-2126
VL - 24
SP - 1719
EP - 1728
JO - Structure
JF - Structure
IS - 10
ER -