One Face, Three Solutions: Structural Convergence in PD-L1 Inhibition across Antibodies, Macrocycles, and Small...

Area of Science:

• Structural biology
• Immunology
• Drug discovery

Background:

• Protein-protein interactions (PPIs) with large, flat interfaces, like PD-1/PD-L1, are difficult drug targets.
• The PD-1/PD-L1 immune checkpoint interaction involves an extended β-sheet surface, posing a significant challenge for drug development.

Purpose of the Study:

• To present a comparative, structure-driven analysis of PD-L1 complexes.
• To demonstrate a unified structural framework for understanding PD-L1 inhibition across different therapeutic modalities.
• To reveal modality-agnostic design principles for targeting flat immune checkpoint PPIs.

Main Methods:

• Comparative analysis of PD-L1 complexes from the Protein Data Bank.
• Visualization and quantitative comparison of interface overlap, hotspot conservation, and buried surface area.
• Structure-driven analysis of antibodies, macrocyclic peptides, and small molecules targeting PD-L1.

Main Results:

• All effective PD-L1 inhibitors engage the same CC'FG β-sheet face.
• Antibodies directly block the interface, macrocycles mimic antibody coverage, and small molecules induce homodimerization.
• Distinct inhibitory modalities converge on the same functional CC'FG hotspot region through different mechanisms.

Conclusions:

• A unified structural framework explains PD-L1 inhibition across diverse drug types.
• Structure-guided principles can facilitate the rational design of next-generation PD-L1 modulators.
• Understanding the convergence on the CC'FG hotspot enables broader strategies for targeting flat PPIs.