Structure and Dynamics of PD-L1 and an Ultra-High-Affinity PD-1 Receptor Mutant
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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.
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Several PD-L1-targeting designs generated by constrained hallucination with PD-1 binding motifs followed by Rosetta design had binding affinities in the mid-nanomolar range.
“Several designs targeting PD-L1 generated by constrained hallucination with binding motifs derived from PD-1 (Table S1) (15), followed by Rosetta design, were found to have binding affinities in the mid-nanomolar range (Fig. S1B–E).”
From Scaffolding protein functional sites using deep learning (2022) · cites this paper as [15]
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- Authors
- Pascolutti, R., Sun, X., Kao, J., Maute, R. L., Ring, A. M., Bowman, G. R., & Kruse, A. C.
- Affiliations
- Harvard University (US)
- Washington University in St. Louis (US)
- Yale University (US)
- Corresponding author
- Kruse, Andrew C.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 24
- Issue
- 10
- Pages
- 1719-1728
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC5052120
- OpenAlex
- W2520448851
- Cited by
- 102
- References
- 35
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 15 · 2023: 13 · 2022: 7 · 2021: 9 · 2020: 15 · 2019: 13 · 2018: 7 · 2017: 8
- FWCI
- 5.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (1DP5OD021345)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Keywords
- PD-1, PD-L1, immune checkpoint, ligand-receptor interactions, binding affinity enhancement, point mutations, polar interactions, conformational dynamics, pH-dependent binding, tumor microenvironment, antitumor immunity
- MeSH terms
- Binding Sites, Humans, Hydrogen-Ion Concentration, Models, Molecular, Protein Binding, Point Mutation, Protein Structure, Secondary, Crystallography, X-Ray, Molecular Dynamics Simulation, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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