9BBJ

M. tuberculosis ClpC1-NTD complexed with a click chemistry analog of Rufomycin

これはPDB形式変換不可エントリーです。

9BBJ の概要

• エントリーDOI: 10.2210/pdb9bbj/pdb
• 関連するPDBエントリー: 6cn8 6pbs
• 分子名称: ATP-dependent Clp protease ATP-binding subunit ClpC1, Click chemistry analog of Rufomycin (2 entities in total)
• 機能のキーワード: m. tuberculosis, clpc1, rufomycin, click-chemistry, antibiotic
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 18493.34

構造登録者

Abad-Zapatero, C.,Ratia, K. (登録日: 2024-04-05, 公開日: 2025-12-10, 最終更新日: 2026-01-07)

主引用文献

Ratia, K.,Jin, S.,Abad-Zapatero, C.,Shetye, G.S.,Demissie, R.,Qader, M.,Beautrait, A.,Nikolic, D.S.,Wolf, N.M.,Rubin, E.J.,Krandor, O.,Serbina, N.,Li, G.,Pauli, G.F.,Klein, L.L.,Cho, S.,Franzblau, S.G.,Fotouhi, N.,Kaneko, T.,Lee, H.
Unique Interactions of Novel Rufomycin "Click Chemistry" Analogs with Mtb ClpC1 and Implications.
J.Med.Chem., 68:26298-26310, 2025

PubMed Abstract: Disrupting protein homeostasis in () by targeting the ClpC1P1P2 proteolytic complex is a promising anti-TB strategy. We synthesized conformationally constrained monomeric and dimeric rufomycin 4/6 (RUF) analogs via click chemistry. While most monomeric analogs were inactive, dimeric analogs displayed potent anti- activity. Surface plasmon resonance revealed tight, slow-dissociating binding of dimers to the ClpC1 N-terminal domain (ClpC1), indicating prolonged residency time. X-ray crystallography and size exclusion chromatography demonstrated that dimeric analogs induce NTD dimerization, likely shifting the equilibrium toward enzymatically active hexamers rather than inactive decamers. Dimers enhanced ATPase activity over 10-fold, surpassing that of ecumicin (8-fold) and far exceeding RUF (<2-fold). Notably, our dimers bind two NTDs per molecule (1:2), contrasting with RUF (1:1) and ecumicin (2:1), suggesting a distinct activation mechanism. These RUF-based click chemistry dimers represent potent ClpC1 modulators with extended residency and novel stoichiometry, offering promising tools for studying protein degradation.

PubMed: 41384615
DOI: 10.1021/acs.jmedchem.5c02416

実験手法

X-RAY DIFFRACTION (2.56 Å)