7RJF

MOPD-1 mutant-L47W

7RJF の概要

• エントリーDOI: 10.2210/pdb7rjf/pdb
• 分子名称: [L47W]MOPD-1, ZINC ION, MALONATE ION, ... (4 entities in total)
• 機能のキーワード: synthetic peptide, disulfide-rich peptide, antitumor peptide, peptide mimetic, antitumor protein
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 11934.23

構造登録者

Huawu, Y.,Conan, K.W.,Gordon, J.K.,Brett, M.C.,Yen-Hua, H.,David, J.C. (登録日: 2021-07-20, 公開日: 2021-10-27, 最終更新日: 2024-10-23)

主引用文献

Yin, H.,Zhou, X.,Huang, Y.H.,King, G.J.,Collins, B.M.,Gao, Y.,Craik, D.J.,Wang, C.K.
Rational Design of Potent Peptide Inhibitors of the PD-1:PD-L1 Interaction for Cancer Immunotherapy.
J.Am.Chem.Soc., 143:18536-18547, 2021

PubMed Abstract: Peptides have potential to be developed into immune checkpoint inhibitors, but the target interfaces are difficult to inhibit. Here, we explored an approach to mimic the binding surface of PD-1 to design inhibitors. Mimicking native PD-1 resulted in a mimetic with no activity. However, mimicking an affinity-optimized PD-1 resulted in the peptide mimetic MOPD-1 that displayed nanomolar affinity to PD-L1 and could inhibit PD-1:PD-L1 interactions in both protein- and cell-based assays. Mutagenesis and structural characterization using NMR spectroscopy and X-ray crystallography revealed that binding residues from the high affinity PD-1 are crucial for the bioactivity of MOPD-1. Furthermore, MOPD-1 was extremely stable in human serum and inhibited tumor growth , suggesting it has potential for use in cancer immunotherapy. The successful design of an inhibitor of PD-1:PD-L1 using the mimicry approach described herein illustrates the value of placing greater emphasis on optimizing the target interface before inhibitor design and is an approach that could have broader utility for the design of peptide inhibitors for other complex protein-protein interactions.

PubMed: 34661406
DOI: 10.1021/jacs.1c08132

実験手法

X-RAY DIFFRACTION (1.8 Å)