ArticleProceedings of the National Academy of Sciences of the United States of America2019
A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 68 citations in OpenAlex.
- Humanized Anti-PD-1 Antibodies Generated Using The Conditional Kernel-Elastic Autoencoder.bioRxiv : the preprint server for biology · 2026Article
- Computational screening of Viola odorata cyclotides identifies Phyb C as potential PD-1 inhibitor for cancer immunotherapy.Molecular diversity · 2026Article
- Mechanical force regulates the inhibitory function of PD-1.EMBO reports · 2026Article
- Engineering strategies and binding mechanisms of therapeutic anti-PD-1 antibodies approved by regulatory agencies globally.Frontiers in immunology · 2026Review
- In search of novel PD1 inhibitor from natural products by high-throughput virtual screening and molecular dynamics simulation.PloS one · 2026Article
- Targeting PD-1 in Squamous Cell Carcinoma: Flavonoid-based Therapeutics Unveiled throughCurrent computer-aided drug design · 2026Article
- Deep Mutational Scanning in Immunology: Techniques and Applications.Pathogens (Basel, Switzerland) · 2025Review
- Allosteric inhibition of the IZUMO1-JUNO fertilization complex by the naturally occurring antisperm antibody OBF13.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Soluble Programmed Cell Death-1: A Potential Predictor of HBsAg Loss in Pediatric Patients with Chronic Hepatitis B Undergoing Peginterferon Therapy.ImmunoTargets and therapy · 2025Article
- DEPDC1B: A novel tumor suppressor gene associated with immune infiltration in colon adenocarcinoma.Cancer medicine · 2024Article
- Cancer therapy with antibodies.Nature reviews. Cancer · 2024Review
- In Search of Better Peptide-(Derived from PD-L2)-Based Immune Checkpoint Inhibitors.Biomolecules · 2024Article
- GNUV201, a novel human/mouse cross-reactive and low pH-selective anti-PD-1 monoclonal antibody for cancer immunotherapy.BMC immunology · 2024Article
- Engineering PD-1-targeted small protein variants for in vitro diagnostics and in vivo PET imaging.Journal of translational medicine · 2024Article
- Innovative CDR grafting and computational methods for PD-1 specific nanobody design.Frontiers in bioinformatics · 2024Article
- 5-chloro-3-(2-(2,4-dinitrophenyl) hydrazono)indolin-2-one: synthesis, characterization, biochemical and computational screening against SARS-CoV-2.Chemicke zvesti · 2024Article
- Programmed cell death-ligand 2: new insights in cancer.Frontiers in immunology · 2024Review
- Hope and Challenges: Immunotherapy inBiomedicines · 2023Review
- Next Generation CD44v6-Specific CAR-NK Cells Effective against Triple Negative Breast Cancer.International journal of molecular sciences · 2023Article
- Bioactive Compounds from the Mushroom-Forming FungusAntibiotics (Basel, Switzerland) · 2023Article
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Immune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-PD-1 is relatively flat, it harbors a striking pocket in the murine PD-1/PD-L2 structure. An analogous pocket in human PD-1 may serve as a small-molecule drug target, but the structure of the human complex is unknown. Because the CC' and FG loops in murine PD-1 adopt new conformations upon binding PD-L2, we hypothesized that mutations in these two loops could be coupled to pocket formation and alter PD-1's affinity for PD-L2. Here, we conducted deep mutational scanning in these loops and used yeast surface display to select for enhanced PD-L2 binding. A PD-1 variant with three substitutions binds PD-L2 with an affinity two orders of magnitude higher than that of the wild-type protein, permitting crystallization of the complex. We determined the X-ray crystal structures of the human triple-mutant PD-1/PD-L2 complex and the apo triple-mutant PD-1 variant at 2.0 Å and 1.2 Å resolution, respectively. Binding of PD-L2 is accompanied by formation of a prominent pocket in human PD-1, as well as substantial conformational changes in the CC' and FG loops. The structure of the apo triple-mutant PD-1 shows that the CC' loop adopts the ligand-bound conformation, providing support for allostery between the loop and pocket. This human PD-1/PD-L2 structure provide critical insights for the design and discovery of small-molecule PD-1 inhibitors.
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