7WSL

PD-1 in complex with Dostarlimab

Summary for 7WSL

• Entry DOI: 10.2210/pdb7wsl/pdb
• Descriptor: light chain, Programmed cell death protein 1, heavy chain, ... (4 entities in total)
• Functional Keywords: pd-1, dostarlimab, antibody, cancer immunotherapy, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 62804.76

Authors

Heo, Y.S. (deposition date: 2022-01-30, release date: 2022-08-24, Last modification date: 2024-11-06)

Primary citation

Park, U.B.,Jeong, T.J.,Gu, N.,Lee, H.T.,Heo, Y.S.
Molecular basis of PD-1 blockade by dostarlimab, the FDA-approved antibody for cancer immunotherapy.
Biochem.Biophys.Res.Commun., 599:31-37, 2022

PubMed Abstract: Targeting of programmed cell death 1 (PD-1) with monoclonal antibodies to block the interaction with its ligand PD-L1 has been successful in immunotherapy of multiple types of cancer, and their mechanism involves the restoration of the T-cell immune response. April 2021, the US FDA approved dostarlimab, a therapeutic antibody against PD-1, for the treatment of endometrial cancer. Here, we report the crystal structure of the extracellular domain of PD-1 in complex with the dostarlimab Fab at the resolution of 1.53 Å. Although the interaction between PD-1 and dostarlimab involves mainly the residues within the heavy chain of dostarlimab, the steric occlusion of PD-L1 binding is primarily contributed by the light chain. Dostarlimab induces conformational rearrangements of the BC, C'D and FG loops of PD-1 to achieve a high affinity. Significantly, the residue R86 within the C'D loop of PD-1 plays a critical role for dostarlimab binding by occupying the concave surface on the heavy chain via multiple interactions. This high-resolution structure can provide helpful information for designing improved anti-PD-1 biologics or effective combination strategies for cancer immunotherapy.

PubMed: 35168061
DOI: 10.1016/j.bbrc.2022.02.026

Experimental method

X-RAY DIFFRACTION (1.534 Å)