Division of Applied Life Science (BK21 Program), Systems and Synthetic Agrobiotech Center (SSAC), Research Institute of Natural Science (RINS), Gyeongsang National University, Jinju, South Korea.
PLoS One. 2013;8(3):e59278. doi: 10.1371/journal.pone.0059278. Epub 2013 Mar 20.
Sirtuin belongs to a family of typical histone deacetylase which regulates the fundamental cellular biological processes including gene expression, genome stability, mitosis, nutrient metabolism, aging, mitochondrial function, and cell motility. Michael et. al. reported that B-site mutation (Q167A and H187A) decreased the SIRT2 activity but still the structural changes were not reported. Hence, we performed 5 ns molecular dynamics (MD) simulation on SIRT2 Apo-form and complexes with substrate/NAD(+) and inhibitor of wild type (WT), Q167A, and H187A. The results revealed that the assembly and disassembly of C-site induced by presence of substrate/NAD(+) and inhibitor, respectively. This assembly and disassembly was mainly due to the interaction between the substrate/NAD(+) and inhibitor and F96 and the distance between F96 and H187 which are present at the neck of the C-site. MD simulations suggest that the conformational change of L3 plays a major role in assembly and disassembly of C-site. Our current results strongly suggest that the distinct conformational change of L3 as well as the assembly and disassembly of C-site plays an important role in SIRT2 deacetylation function. Our study unveiled the structural changes of SIRT2 in presence of NAD(+) and inhibitor which should be helpful to improve the inhibitory potency of SIRT2.
Sirtuin 属于典型的组蛋白去乙酰化酶家族，调节包括基因表达、基因组稳定性、有丝分裂、营养代谢、衰老、线粒体功能和细胞迁移在内的基本细胞生物学过程。Michael 等人报道 B 位突变（Q167A 和 H187A）降低了 SIRT2 的活性，但仍未报道结构变化。因此，我们对 SIRT2 apo 形式以及与野生型（WT）、Q167A 和 H187A 的底物/NAD(+)和抑制剂的复合物进行了 5 ns 分子动力学（MD）模拟。结果表明，存在底物/NAD(+)和抑制剂时分别诱导 C 位的组装和拆卸。这种组装和拆卸主要是由于底物/NAD(+)和抑制剂与 F96 和位于 C 位颈部的 F96 和 H187 之间的距离之间的相互作用。MD 模拟表明，L3 的构象变化在 C 位的组装和拆卸中起着主要作用。我们目前的结果强烈表明，L3 的明显构象变化以及 C 位的组装和拆卸在 SIRT2 去乙酰化功能中起着重要作用。我们的研究揭示了 NAD(+)和抑制剂存在下 SIRT2 的结构变化，这应该有助于提高 SIRT2 的抑制效力。
