Small-molecule activators of the Staphylococcus aureus ClpC/ClpP AAA+ protease.

IF 4.5 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2026-09-22 eCollection Date: 2026-10-16 DOI:10.1016/j.isci.2026.117738

Timo Jenne, Vsevolod Viliuga, Ulrike Uhrig, Britta Jehle, Merlin Schwan, Jürgen Kopp, Dirk Flemming, Elisabeth Seebach, Irmgard Sinning, Bernd Bukau, Axel Mogk

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引用次数: 0

Abstract

The central AAA+ ClpC/ClpP protease in Gram-positive bacteria is crucial for virulence and stress resistance and has been recognized as drug target. Natural cyclic peptides deregulate the essential Mycobacterium tuberculosis ClpC1 and cause cell death. Similarly, overactivated mutants of the non-essential Staphylococcus aureus ClpC homolog cause uncontrolled proteolysis and severe toxicity in vivo. However, no chemical modulators of S. aureus ClpC have been described. Here, using a biochemical high-throughput screen, we identify eight distinct bona fide small molecules that stimulate ClpC ATPase and proteolytic activity in vitro. Structural, computational, and mutational analyses define two ligandable regulatory sites within the ClpC N-terminal domain (NTD) as compound targets: a conserved hydrophobic groove and an allosteric pArg1 pocket, both engaged in substrate recognition. These findings establish S. aureus ClpC as chemically targetable and provide mechanistic insight into its regulatory architecture, enabling future development and optimization of chemical probes to deregulate AAA+ protease control.

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金黄色葡萄球菌ClpC/ClpP AAA+蛋白酶的小分子激活剂。

革兰氏阳性菌的中心AAA+ ClpC/ClpP蛋白酶对毒力和抗逆性至关重要，已被认为是药物靶点。天然环肽解除了必要的结核分枝杆菌ClpC1的调控并导致细胞死亡。同样，非必需的金黄色葡萄球菌ClpC同源物的过度激活突变体在体内引起不受控制的蛋白水解和严重的毒性。然而，金黄色葡萄球菌ClpC的化学调节剂尚未被描述。在这里，使用生化高通量筛选，我们确定了八种不同的真正的小分子，在体外刺激ClpC atp酶和蛋白水解活性。结构、计算和突变分析将ClpC n端结构域（NTD）内的两个可配体调控位点定义为复合靶标：一个保守的疏水槽和一个变构pArg1口袋，它们都参与底物识别。这些发现确定了金黄色葡萄球菌ClpC具有化学靶向性，并为其调控结构提供了机制见解，为未来开发和优化化学探针以解除AAA+蛋白酶控制提供了可能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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