Discovery of an autoinhibited conformation in mesotrypsin reveals a strategy for selective serine protease inhibition

IF 11.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Matt Coban, Mahesh Gokara, Luis M. Forero Vargas, Sarah D. Tanzer, Sherry X. Zhou, Alexandra Hockla, Banumathi Sankaran, Thomas R. Caulfield, Evette S. Radisky
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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.

Abstract Image

发现中胰蛋白酶的自抑制构象揭示了选择性丝氨酸蛋白酶抑制的策略
选择性抑制超过100种S1家族丝氨酸蛋白酶是一个长期的挑战,因为它们的活性位点相似。与癌症进展有关的中胰蛋白酶就是这些困难的例证;目前还没有抑制剂比其他人类胰蛋白酶具有选择性。我们通过x射线晶体学发现了一个意想不到的中胰蛋白酶的自抑制构象,在活性位点附近发现了一个隐藏的口袋。通过高通量虚拟筛选,我们确定了一种构象选择性的小分子抑制剂,可以稳定中胰蛋白酶的失活状态。该抑制剂对中胰蛋白酶的选择性优于其他胰蛋白酶。我们的研究结果挑战了消化胰蛋白酶作为缺乏变构调节潜力的组成活性酶的公认观点。此外,对其他结构的分析表明,具有类似变构隐口袋的封闭状态的动态采样在S1丝氨酸蛋白酶中广泛存在。这些观察结果指出了一种潜在的可推广的策略来实现选择性抑制,为针对癌症和其他疾病的丝氨酸蛋白酶的药物开发提供了广泛的意义。
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来源期刊
Science Advances
Science Advances 综合性期刊-综合性期刊
CiteScore
21.40
自引率
1.50%
发文量
1937
审稿时长
29 weeks
期刊介绍: Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.
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