6HWN

Structure of Thermus thermophilus ClpP in complex with a tripeptide.

6HWN の概要

• エントリーDOI: 10.2210/pdb6hwn/pdb
• 分子名称: ATP-dependent Clp protease proteolytic subunit, Unknown tripeptide, DI(HYDROXYETHYL)ETHER, ... (4 entities in total)
• 機能のキーワード: hydrolase, complex, activator
• 由来する生物種: Thermus thermophilus; 詳細
• タンパク質・核酸の鎖数: 14
• 化学式量合計: 163059.08

構造登録者

Felix, J.,Schanda, P.,Fraga, H.,Morlot, C. (登録日: 2018-10-12, 公開日: 2019-09-18, 最終更新日: 2024-01-24)

主引用文献

Felix, J.,Weinhaupl, K.,Chipot, C.,Dehez, F.,Hessel, A.,Gauto, D.F.,Morlot, C.,Abian, O.,Gutsche, I.,Velazquez-Campoy, A.,Schanda, P.,Fraga, H.
Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors.
Sci Adv, 5:eaaw3818-eaaw3818, 2019

PubMed Abstract: Coordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. Caseinolytic protease (ClpP) is a tetradecameric complex, which has emerged as a drug target against multiple pathogenic bacteria. Activation of different ClpPs by inhibitors has been independently reported from drug development efforts, but no rationale for inhibitor-induced activation has been hitherto proposed. Using an integrated approach that includes x-ray crystallography, solid- and solution-state nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the proteasome inhibitor bortezomib binds to the ClpP active-site serine, mimicking a peptide substrate, and induces a concerted allosteric activation of the complex. The bortezomib-activated conformation also exhibits a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism, where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association and protein processive degradation.

PubMed: 31517045
DOI: 10.1126/sciadv.aaw3818

実験手法

X-RAY DIFFRACTION (1.95 Å)