College of Chemistry, Fuzhou University, Fuzhou, P.R. China.
Fujian Key Laboratory of Marine Enzyme Engineering, Fuzhou University, Fuzhou, P.R. China.
FASEB J. 2021 Feb;35(2):e21259. doi: 10.1096/fj.202002139RR.
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.
丝氨酸蛋白酶是一个庞大的酶家族，对多种生理过程至关重要，并且已被证明是多种临床适应症的诊断和治疗靶点。不同丝氨酸蛋白酶的活性位点具有高度相似性，这给针对活性位点的丝氨酸蛋白酶抑制剂达到高选择性带来了挑战。在这里，我们通过调查包括我们在内的最新研究工作，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，这种方法可以达到很高的特异性。自溶环在不同的丝氨酸蛋白酶之间高度可变，这解释了针对自溶环的抑制剂的高特异性。我们还概述了将自溶环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，可以用作开发药理学制剂的一般手段，以干预丝氨酸蛋白酶的活性，例如在血液凝固中。
