Structural Bioinformatics Laboratory, Faculty of Science and Engineering, Biochemistry, Åbo Akademi University, Turku 20520, Finland.
Institute for Biological Instrumentation of the Russian Academy of Sciences, Federal Research Center "Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences", Pushchino 142290, Russia; Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
Int J Biol Macromol. 2020 Dec 15;165(Pt A):1438-1446. doi: 10.1016/j.ijbiomac.2020.10.022. Epub 2020 Oct 12.
There are several families of cysteine proteinases with different folds - for example the (chymo)trypsin fold family and papain-like fold family - but in both families the hydrolase activity of cysteine proteinases requires a cysteine residue as the catalytic nucleophile. In this work, we have analyzed the topology of the active site regions in 146 three-dimensional structures of proteins belonging to the Papain-like Cysteine Proteinase (PCP) superfamily, which includes papain as a typical representative of this protein superfamily. All analyzed enzymes contain a unique structurally closed conformation - a "PCP-Zone" - which can be divided into two groups, Class A and Class B. Eight structurally conserved amino acids of the PCP-Zone form a common Structural Core. The Structural Core, catalytic nucleophile, catalytic base and residue Xaa - which stabilizes the side-chain conformation of the catalytic base - make up a PCP Structural Catalytic Core (PCP-SCC). The PCP-SCC of Class A and Class B are divided into 5 and 2 types, respectively. Seven variants of the mutual arrangement of the amino-acid side chains of the catalytic triad - nucleophile, base and residue Xaa - within the same fold clearly demonstrate how enzymes with the papain-like fold adapt to the need to perform diverse functions in spite of their limited structural diversity. The roles of both the PCP-Zone of SARS-CoV-2-PLpro described in this study and the NBCZone of SARS-CoV-2-3CLpro presented in our earlier article (Denesyuk AI, Johnson MS, Salo-Ahen OMH, Uversky VN, Denessiouk K. Int J Biol Macromol. 2020;153:399-411) that are in contacts with inhibitors are discussed.
有几个胱氨酸蛋白酶家族具有不同的折叠结构——例如糜蛋白酶折叠家族和木瓜蛋白酶样折叠家族——但在这两个家族中，胱氨酸蛋白酶的水解酶活性都需要半胱氨酸残基作为催化亲核基团。在这项工作中，我们分析了属于木瓜蛋白酶样半胱氨酸蛋白酶（PCP）超家族的 146 个三维蛋白质结构的活性位点区域的拓扑结构，其中包括木瓜蛋白酶作为该蛋白质超家族的典型代表。所有分析的酶都含有一个独特的结构封闭构象——“PCP 区”——它可以分为两类，A 类和 B 类。PCP 区的 8 个结构保守的氨基酸形成一个共同的结构核心。结构核心、催化亲核基团、催化碱和残基 Xaa——它稳定催化碱的侧链构象——构成 PCP 结构催化核心（PCP-SCC）。A 类和 B 类的 PCP-SCC 分别分为 5 类和 2 类。催化三联体的氨基酸侧链在相同折叠内的相互排列的七种变体——亲核基团、碱基和残基 Xaa——清楚地表明，尽管结构多样性有限，但具有木瓜蛋白酶样折叠的酶如何适应执行不同功能的需要。本研究中描述的 SARS-CoV-2-PLpro 的 PCP 区和我们之前的文章（Denesyuk AI、Johnson MS、Salo-Ahen OMH、Uversky VN、Denessiouk K. Int J Biol Macromol. 2020;153:399-411）中描述的 SARS-CoV-2-3CLpro 的 NBCZone 与抑制剂相互作用的作用都进行了讨论。
