7OUN

Structure of human PD-L1 in complex with macrocyclic inhibitor

Summary for 7OUN

• Entry DOI: 10.2210/pdb7oun/pdb
• Descriptor: Programmed cell death 1 ligand 1, macrocyclic peptide (3 entities in total)
• Functional Keywords: programmed death ligand 1, immune checkpoint inhibitor, cancer, cell cycle, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 16494.92

Authors

Zyla, E.,Dubin, G. (deposition date: 2021-06-12, release date: 2021-09-15, Last modification date: 2024-10-23)

Primary citation

Zyla, E.,Musielak, B.,Holak, T.A.,Dubin, G.
Structural Characterization of a Macrocyclic Peptide Modulator of the PD-1/PD-L1 Immune Checkpoint Axis.
Molecules, 26:-, 2021

PubMed Abstract: The clinical success of PD-1/PD-L1 immune checkpoint targeting antibodies in cancer is followed by efforts to develop small molecule inhibitors with better penetration into solid tumors and more favorable pharmacokinetics. Here we report the crystal structure of a macrocyclic peptide inhibitor (peptide 104) in complex with PD-L1. Our structure shows no indication of an unusual bifurcated binding mode demonstrated earlier for another peptide of the same family (peptide 101). The binding mode relies on extensive hydrophobic interactions at the center of the binding surface and an electrostatic patch at the side. An interesting sulfur/π interaction supports the macrocycle-receptor binding. Overall, our results allow a better understanding of forces guiding macrocycle affinity for PD-L1, providing a rationale for future structure-based inhibitor design and rational optimization.

PubMed: 34443436
DOI: 10.3390/molecules26164848

Experimental method

X-RAY DIFFRACTION (1.9 Å)