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首页> 外文期刊>Journal of Molecular Biology >In silico discovery of enzyme-substrate specificity-determining residue clusters
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In silico discovery of enzyme-substrate specificity-determining residue clusters

机译：在计算机上发现酶-底物特异性的残基簇

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摘要

The binding between an enzyme and its substrate is highly specific, despite the fact that many different enzymes show significant sequence and structure similarity. There must be, then, substrate specificity-determining residues that enable different enzymes to recognize their unique substrates. We reason that a coordinated, not independent, action of both conserved and non-conserved residues determine enzymatic activity and specificity. Here, we present a surface patch ranking (SPR) method for in silico discovery of substrate specificity-determining residue clusters by exploring both sequence conservation and correlated mutations. As case studies we apply SPR to several highly homologous enzymatic protein pairs, such as guanylyl versus adenylyl cyclases, lactate versus malate dehydrogenases, and trypsin versus chymotrypsin. Without using experimental data, we predict several single and multiresidue clusters that are consistent with previous mutagenesis experimental results. Most single-residue clusters are directly involved in enzyme-substrate interactions, whereas multi-residue clusters are vital for domain-domain and regulator-enzyme interactions, indicating their complementary role in specificity determination. These results demonstrate that SPR may help the selection of target residues for mutagenesis experiments and, thus, focus rational drug design, protein engineering, and functional annotation to the relevant regions of a protein. Published by Elsevier Ltd.
机译：尽管许多不同的酶显示出明显的序列和结构相似性，但酶与其底物之间的结合是高度特异性的。因此，必须有确定底物特异性的残基，使不同的酶能够识别其独特的底物。我们认为保守和非保守残基的协调而不是独立的作用决定了酶活性和特异性。在这里，我们提出了一种通过表面活性剂排序（SPR）方法，通过探索序列保守性和相关突变，在计算机上发现底物特异性决定残基簇的方法。作为案例研究，我们将SPR应用于几种高度同源的酶促蛋白对，例如胍基对腺苷酸环化酶，乳酸对苹果酸脱氢酶，以及胰蛋白酶对胰凝乳蛋白酶。在不使用实验数据的情况下，我们预测了与先前诱变实验结果一致的几个单残基和多残基簇。大多数单残基簇直接参与酶-底物相互作用，而多残基簇对于域-域和调节剂-酶相互作用至关重要，表明它们在特异性测定中的互补作用。这些结果表明，SPR可能有助于诱变实验的目标残基的选择，从而将合理的药物设计，蛋白质工程和功能注释集中于蛋白质的相关区域。由Elsevier Ltd.发布

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