PDF(Pubmed)
Abstract：
Small ubiquitin-related modifier (SUMO)-specific protease 1 (SENP1) is a cysteine protease that catalyzes the cleavage of the C-terminus of SUMO1 for the processing of SUMO precursors and deSUMOylation of target proteins. SENP1 is considered to be a promising target for the treatment of hepatocellular carcinoma (HCC) and prostate cancer. SENP1 Gln597 is located at the unstructured loop connecting the helices α4 to α5. The Q597A mutation of SENP1 allosterically disrupts the hydrolytic reaction of SUMO1 through an unknown mechanism. Here, extensive multiple replicates of microsecond molecular dynamics (MD) simulations, coupled with principal component analysis, dynamic cross-correlation analysis, community network analysis, and binding free energy calculations, were performed to elucidate the detailed mechanism. Our MD simulations showed that the Q597A mutation induced marked dynamic conformational changes in SENP1, especially in the unstructured loop connecting the helices α4 to α5 which the mutation site occupies. Moreover, the Q597A mutation caused conformational changes to catalytic Cys603 and His533 at the active site, which might impair the catalytic activity of SENP1 in processing SUMO1. Moreover, binding free energy calculations revealed that the Q597A mutation had a minor effect on the binding affinity of SUMO1 to SENP1. Together, these results may broaden our understanding of the allosteric modulation of the SENP1-SUMO1 complex.
摘要：
小泛素相关修饰剂（SUMO）特异性蛋白酶1（SENP1）是一种半胱氨酸蛋白酶，可催化SUMO1C末端的裂解，用于加工SUMO前体和靶蛋白的去SUMO化。SENP1被认为是治疗肝细胞癌（HCC）和前列腺癌的有希望的靶标。SENP1Gln597位于连接螺旋α4至α5的非结构化环路处。SENP1的Q597A突变通过未知的机制以变构方式破坏SUMO1的水解反应。这里,微秒分子动力学(MD)模拟的大量重复，结合主成分分析，动态互相关分析，社区网络分析，和结合自由能计算，进行以阐明详细的机制。我们的MD模拟表明，Q597A突变在SENP1中引起了明显的动态构象变化，尤其是在连接突变位点所占据的螺旋α4至α5的非结构化环中。此外，Q597A突变引起活性位点催化Cys603和His533的构象变化，这可能会损害SENP1在加工SUMO1中的催化活性。此外，结合自由能计算显示,Q597A突变对SUMO1与SENP1的结合亲和力影响较小.一起,这些结果可能会拓宽我们对SENP1-SUMO1复合物的变构调制的理解.
