Computational design of a synthetic PD-1 agonist

Cassie M. Bryan*, Gabriel J. Rocklin, Matthew J. Bick, Alex Ford, Sonia Majri-Morrison, Ashley V. Kroll, Chad J. Miller, Lauren Carter, Inna Goreshnik, Alex Kang, Frank DiMaio, Kristin V. Tarbell, David Baker

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Programmed cell death protein-1 (PD-1) expressed on activated T cells inhibits T cell function and proliferation to prevent an excessive immune response, and disease can result if this delicate balance is shifted in either direction. Tumor cells often take advantage of this pathway by overexpressing the PD-1 ligand PD-L1 to evade destruction by the immune system. Alternatively, if there is a decrease in function of the PD-1 pathway, unchecked activation of the immune system and autoimmunity can result. Using a combination of computation and experiment, we designed a hyperstable 40-residue miniprotein, PD-MP1, that specifically binds murine and human PD-1 at the PD-L1 interface with a Kd of ∼100 nM. The apo crystal structure shows that the binder folds as designed with a backbone RMSD of 1.3 Å to the design model. Trimerization of PD-MP1 resulted in a PD-1 agonist that strongly inhibits murine T cell activation. This small, hyperstable PD-1 binding protein was computationally designed with an all-beta interface, and the trimeric agonist could contribute to treatments for autoimmune and inflammatory diseases.

Original languageEnglish (US)
Article numbere2102164118
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number29
StatePublished - Jul 20 2021
Externally publishedYes


  • Protein design | PD-1 | autoimmunity | immunotherapy

ASJC Scopus subject areas

  • General


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