Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAAC), Gyeongsang National University (GNU), Gazha-dong, Jinju, Republic of Korea.
J Biomol Struct Dyn. 2012;30(3):235-54. doi: 10.1080/07391102.2012.680026. Epub 2012 Jun 12.
Sirtuin is a member of NAD(+)-dependent deacetylase family. The structural details of Sirtuin 2 (SIRT2) complex will be very useful to discover the drug which might have beneficial effects on various diseases like cancer, diabetes, etc. Unfortunately, SIRT2 complex structure is not available yet, hence molecular docking was carried out to dock the substrate (NAD(+) and acetylated lysine) and inhibitor (sirtinol) in the NAD(+) binding site. The suitable binding orientation of substrate and inhibitor in the SIRT2 active site was selected and subjected to 5 ns molecular dynamics simulations to adjust the binding orientation of inhibitor and substrate as well as to identify the conformational changes in the active site. The result provides an insight about 3D SIRT2 structural details as well as the importance of F96 in deacetylation function. In addition, our simulations revealed the displacement of F96 upon substrate and inhibitor binding, inducing an extended conformation of loop3 and changing its interactions with the rest of SIRT2. We believe that our study could be helpful to gain a structural insight of SIRT2 and to design the receptor-based inhibitors.
Sirtuin 是 NAD(+)-依赖性脱乙酰酶家族的成员。Sirtuin 2 (SIRT2) 复合物的结构细节对于发现可能对癌症、糖尿病等各种疾病有有益影响的药物将非常有用。不幸的是，SIRT2 复合物的结构尚不可用，因此进行了分子对接，以将底物（NAD(+)和乙酰化赖氨酸）和抑制剂（sirtinol）对接在 NAD(+)结合位点上。选择了底物和抑制剂在 SIRT2 活性位点中的合适结合取向，并进行了 5 ns 的分子动力学模拟，以调整抑制剂和底物的结合取向，并确定活性位点中的构象变化。结果提供了对 3D SIRT2 结构细节的深入了解，以及 F96 在去乙酰化功能中的重要性。此外，我们的模拟揭示了底物和抑制剂结合时 F96 的位移，导致 loop3 伸展构象，并改变其与 SIRT2 其余部分的相互作用。我们相信，我们的研究可以帮助深入了解 SIRT2 的结构，并设计基于受体的抑制剂。
