CAS Key Laboratory of Receptor Research; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
College of Mathematics and Physics, Shanghai University of Electric Power, Shanghai 200090, China.
J Chem Inf Model. 2021 May 24;61(5):2499-2508. doi: 10.1021/acs.jcim.1c00318. Epub 2021 May 2.
Enzyme activity is affected by amino acid mutations, particularly mutations near the active site. Increasing evidence has shown that distal mutations more than 10 Å away from the active site may significantly affect enzyme activity. However, it is difficult to study the enzyme regulation mechanism of distal mutations due to the lack of a systematic collection of three-dimensional (3D) structures, highlighting distal mutation site and the corresponding enzyme activity change. Therefore, we constructed a distal mutation database, namely, D3DistalMutation, which relates the distal mutation to enzyme activity. As a result, we observed that approximately 80% of distal mutations could affect enzyme activity and 72.7% of distal mutations would decrease or abolish enzyme activity in D3DistalMutation. Only 6.6% of distal mutations in D3DistalMutation could increase enzyme activity, which have great potential to the industrial field. Among these mutations, the Y to F, S to D, and T to D mutations are most likely to increase enzyme activity, which sheds some light on industrial catalysis. Distal mutations decreasing enzyme activity in the allosteric pocket play an indispensable role in allosteric drug design. In addition, the pockets in the enzyme structures are provided to explore the enzyme regulation mechanism of distal mutations. D3DistalMutation is accessible free of charge at https://www.d3pharma.com/D3DistalMutation/index.php.
酶活性受氨基酸突变的影响，特别是靠近活性部位的突变。越来越多的证据表明，距离活性部位超过 10Å 的远端突变可能显著影响酶活性。然而，由于缺乏对三维（3D）结构的系统收集，很难研究远端突变对酶活性的调节机制，突出了远端突变位点和相应的酶活性变化。因此，我们构建了一个远端突变数据库，即 D3DistalMutation，它将远端突变与酶活性联系起来。结果表明，大约 80%的远端突变可以影响酶活性，而在 D3DistalMutation 中，72.7%的远端突变会降低或消除酶活性。D3DistalMutation 中只有 6.6%的远端突变可以增加酶活性，这对工业领域具有很大的潜力。在这些突变中，Y 到 F、S 到 D 和 T 到 D 的突变最有可能增加酶活性，这为工业催化提供了一些启示。变构口袋中降低酶活性的远端突变在变构药物设计中起着不可或缺的作用。此外，还提供了酶结构中的口袋，以探索远端突变对酶活性的调节机制。D3DistalMutation 可在 https://www.d3pharma.com/D3DistalMutation/index.php 免费获取。
