9MDO

Crystal Structure of Y559A Prosegment Binding Loop Mutant of C0362 (TDE_0362 [TDE0362] resi 205-647)

9MDO の概要

• エントリーDOI: 10.2210/pdb9mdo/pdb
• 関連するPDBエントリー: 9ARC 9MDK 9MDM
• 分子名称: Bacterial Ig-like domain protein C0362, 1,2-ETHANEDIOL, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: papain-superfamily cysteine protease, virulence factor, tde_0362, alpha/beta hydrolase, hydrolase
• 由来する生物種: Treponema denticola
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 56539.38

構造登録者

Clark, N.D.,Malkowski, M.G. (登録日: 2024-12-05, 公開日: 2025-02-12)

主引用文献

Clark, N.D.,Li, C.,Malkowski, M.G.
Structural insights into the role of the prosegment binding loop in a papain-superfamily cysteine protease from Treponema denticola.
Acta Crystallogr.,Sect.F, 81:53-61, 2025

PubMed Abstract: Periodontal diseases afflict 20-50% of the global population and carry serious health and economic burdens. Chronic periodontitis is characterized by inflammation of the periodontal pocket caused by dysbiosis. This dysbiosis is coupled with an increase in the population of Treponema denticola, a spirochete bacterium with high mobility and invasivity mediated by a number of virulence factors. One such virulence factor is TDE0362, a multidomain protein with a carboxy-terminal papain-superfamily cysteine protease (C0362). Most papain-superfamily cysteine proteases are produced as proenzymes with a prodomain that interacts with the prosegment binding loop (PBL), requiring proteolytic processing for full activation. Previous studies have indicated that C0362 is not produced as a proenzyme, suggesting an alternative regulatory mechanism. We previously determined the crystal structure of C0362 captured in an inactive conformation with an oxidized catalytic cysteine and a disordered PBL. In this follow-up study, we evaluated the active-site architecture and the PBL in two mutant (Y559A and C412S) structures and an inhibitor-bound (E64) structure to provide insight into the role that the PBL plays in the generation of active enzyme. Our results implicate Tyr559 as playing a critical role in the transition of the enzyme to an active state. We subsequently utilized the structural information to generate models of C0362 bound to human complement factors C3 and C4. Collectively, our results provide insight into the regulatory mechanism and putative substrate-binding interfaces of C0362, highlighting avenues of further research towards inhibition of this essential virulence factor.

PubMed: 39846228
DOI: 10.1107/S2053230X25000378

実験手法

X-RAY DIFFRACTION (2.02 Å)