8YTE

Crystal Structure of TrkA D5 domain in complex with macrocyclic peptide

8YTE の概要

• エントリーDOI: 10.2210/pdb8yte/pdb
• 分子名称: High affinity nerve growth factor receptor, Macrocyclic Peptide, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: transferase, cyclic peptide
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 26391.68

構造登録者

Yamada, T.,Mihara, K.,Ueda, T.,Yamauchi, D.,Shimizu, M.,Ando, A.,Mayumi, K.,Nakata, Z.,Mikamiyama, H. (登録日: 2024-03-25, 公開日: 2024-07-10, 最終更新日: 2024-07-24)

主引用文献

Yamada, T.,Mihara, K.,Ueda, T.,Yamauchi, D.,Shimizu, M.,Ando, A.,Mayumi, K.,Nakata, Z.,Mikamiyama, H.
Discovery and Hit to Lead Optimization of Macrocyclic Peptides as Novel Tropomyosin Receptor Kinase A Antagonists.
J.Med.Chem., 67:11197-11208, 2024

PubMed Abstract: Tropomyosin receptor kinases (Trks) are receptor tyrosine kinases activated by neurotrophic factors, called neurotrophins. Among them, TrkA interacts with the nerve growth factor (NGF), which leads to pain induction. mRNA-display screening was carried out to discover a hit compound , which inhibits protein-protein interactions between TrkA and NGF. Subsequent structure optimization improving phosphorylation inhibitory activity and serum stability was pursued using a unique process that took advantage of the peptide being synthesized by translation from mRNA. This gave peptide , which showed an analgesic effect in a rat incisional pain model. The peptides described here can serve as a new class of analgesics, and the structure optimization methods reported provide a strategy for discovering new peptide drugs.

PubMed: 38950284
DOI: 10.1021/acs.jmedchem.4c00715

実験手法

X-RAY DIFFRACTION (2.26 Å)