9BOT

Human mesotrypsin (PRSS3) unliganded and in autoinhibited (E*) conformation

9BOT の概要

• エントリーDOI: 10.2210/pdb9bot/pdb
• 関連するPDBエントリー: 9BOS
• 分子名称: Trypsin-3, SULFATE ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: serine protease, autoinhibited, conformational variability, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24670.82

構造登録者

Coban, M.,Sankaran, B.,Radisky, E.S. (登録日: 2024-05-06, 公開日: 2025-06-11, 最終更新日: 2025-07-16)

主引用文献

Coban, M.,Gokara, M.,Forero Vargas, L.M.,Tanzer, S.D.,Zhou, S.X.,Hockla, A.,Sankaran, B.,Caulfield, T.R.,Radisky, E.S.
Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition.
Sci Adv, 11:eadu9129-eadu9129, 2025

PubMed Abstract: Selective inhibition of the more than 100 S1 family serine proteases is a long-standing challenge due to their active site similarity. Mesotrypsin, implicated in cancer progression, exemplifies these difficulties; no current inhibitors achieve selectivity over other human trypsins. We found an unexpected autoinhibited conformation of mesotrypsin via x-ray crystallography, revealing a cryptic pocket adjacent to the active site. Using high-throughput virtual screening targeting this cryptic pocket, we identified a conformationally selective small-molecule inhibitor that stabilizes the inactive state of mesotrypsin. This inhibitor demonstrates selectivity for mesotrypsin over other trypsins. Our findings challenge the accepted view of digestive trypsins as constitutively active enzymes lacking potential for allosteric regulation. Furthermore, analyses of other structures suggest that dynamic sampling of closed states with analogous allosteric cryptic pockets appears widespread among S1 serine proteases. These observations point to a potentially generalizable strategy to achieve selective inhibition, offering broad implications for drug development targeting serine proteases in cancer and other diseases.

PubMed: 40614191
DOI: 10.1126/sciadv.adu9129

実験手法

X-RAY DIFFRACTION (1.6 Å)