Serine proteases are a large family of enzymes critical for multiple physiological processes, and proven diagnostic and therapeutic targets in several clinical indications. The high similarity of active sites among different serine proteases posts a challenge to reach high selectivity for inhibitors of serine proteases targeting at the active site. Here, we demonstrated that one particular surface loop on serine proteases (autolysis loop) can be used to regulate their catalytic activity, through surveying the recent works including ours, and such an approach can reach high specificity. The autolysis loop is highly variable among different serine proteases, explaining the high specificity of inhibitors targeting the autolysis loop. We also outline the structural origin that links the perturbation of the autolysis loop and the inhibition of protease activity. Thus, the autolysis loop appears to be a highly sensitive allosteric site and can be used as a general handle to develop pharmacological agents to intervene with the activities of serine proteases in, eg, blood coagulation.

中文翻译：

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通过靶向自溶环抑制丝氨酸蛋白酶的一般策略

丝氨酸蛋白酶是对多种生理过程至关重要的一大类酶，并且在多种临床适应症中被证明是诊断和治疗靶点。不同丝氨酸蛋白酶之间活性位点的高度相似性对针对活性位点的丝氨酸蛋白酶抑制剂达到高选择性提出了挑战。在这里，我们证明了丝氨酸蛋白酶上的一个特定表面环（自溶环）可用于调节其催化活性，通过调查包括我们在内的近期工作，这种方法可以达到高度特异性。自溶环在不同的丝氨酸蛋白酶之间变化很大，这解释了靶向自溶环的抑制剂的高度特异性。我们还概述了将自溶回路的扰动与蛋白酶活性的抑制联系起来的结构起源。因此，自溶环似乎是一个高度敏感的变构位点，并且可以用作开发药理学试剂以干预丝氨酸蛋白酶在例如血液凝固中的活性的通用句柄。