Related Experiment Video
Updated: Feb 17, 2026
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Understanding the structural and energetic basis of PD-1 and monoclonal antibodies bound to PD-L1: A molecular
Danfeng Shi1, Shuangyan Zhou2, Xuewei Liu1
1State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
Background:
The inhibitors blocking the interaction between programmed cell death protein 1(PD-1) and programmed death-ligand 1(PD-L1) can activate the immune response of T cell and eliminate cancer cells. The crystallographic studies have provided structural insights of the interactive interfaces between PD-L1 and its protein ligands. However, the hotspot residues on PD-L1 as well as structural and energetic basis for different protein ligands still need to be further investigated.
Methods:
Molecular modeling methods including molecular dynamics simulation, per-residue free energy decomposition, virtual alanine scanning mutagenesis and residue-residue contact analysis were used to qualitatively and quantitatively analyze the interactions between PD-L1 and different protein ligands.
Results:
The results of virtual alanine scanning mutagenesis suggest that Y56, Q66, M115, D122, Y123, R125 are the hotspot residues on PD-L1. The residue-residue contact analysis further shows that PD-1 interacts with PD-L1 mainly by F and G strands while monoclonal antibodies like avelumab and BMS-936559 mainly interact with PD-L1 by CDR2 and CDR3 loops of the heavy chain.
Conclusions:
A structurally similar β-hairpin peptide with 13 or 14 residues was extracted from each protein ligand and these β-hairpin peptides were found tightly binding to the putative hotspot residues on PD-L1.
General Significance:
This study recognizes the hotspot residues on PD-L1 and uncovers the common structural and energetic basis of different protein ligands binding to PD-L1. These results will be valuable for the design of small molecule or peptide inhibitors targeting on PD-L1.
Insights
This study identifies key "hotspot" residues on PD-L1 crucial for its interaction with cancer-fighting proteins. Understanding these interactions aids in designing new drugs targeting PD-L1 for cancer immunotherapy.
Area of Science:
- Immunology
- Structural Biology
- Computational Chemistry
Background:
- Immune checkpoint inhibitors targeting PD-1/PD-L1 interactions activate T cells to eliminate cancer cells.
- Crystallography offers insights into PD-L1 binding interfaces, but hotspot residues and ligand-specific interactions require further study.
Purpose of the Study:
- To identify hotspot residues on PD-L1.
- To elucidate the structural and energetic basis of PD-L1 interactions with various protein ligands.
- To inform the development of novel PD-L1 inhibitors.
Main Methods:
- Molecular dynamics simulations.
- Per-residue free energy decomposition.
- Virtual alanine scanning mutagenesis.
- Residue-residue contact analysis.
Main Results:
- Identified Y56, Q66, M115, D122, Y123, R125 as key hotspot residues on PD-L1.
- PD-1 binds PD-L1 via F and G strands; antibodies (avelumab, BMS-936559) bind via heavy chain CDR2/CDR3 loops.
- Extracted β-hairpin peptides from ligands bind tightly to PD-L1 hotspots.
Conclusions:
- Recognized critical hotspot residues on PD-L1.
- Uncovered common structural and energetic principles for PD-L1 ligand binding.
- Findings support the design of small molecule and peptide inhibitors targeting PD-L1.
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