<br>使用分子动力学模拟破译 SIRT6 的变构激活机制,Journal of Chemical Information and Modeling

当前位置： X-MOL 学术 › J. Chem. Inf. Model. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

使用分子动力学模拟破译 SIRT6 的变构激活机制
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2023-08-31 , DOI: 10.1021/acs.jcim.3c00227
Zhiyuan Zhao ₁ , Jintong Du _{1,

2} , Yu Du ₁ , Yuan Gao ₁ , Mingxuan Yu ₁ , Yingkai Zhang _{3,

4} , Hao Fang ₁ , Xuben Hou ₁

Affiliation

作为组蛋白脱乙酰酶蛋白家族的一员，NAD ⁺依赖的SIRT6在维持基因组稳定性和调节细胞代谢方面发挥着重要作用。有趣的是，SIRT6被发现相对于脱乙酰化更倾向于水解长链脂肪酰基，并且它可以被脂肪酸激活。然而，SIRT6 识别不同底物并被小分子激活剂激活的机制仍不清楚。在这项研究中，我们进行了广泛的分子动力学模拟，以阐明这些机制。我们的结果表明，肉豆蔻酰化底物的结合稳定了 NAD ⁺的催化有利构象，而乙酰基赖氨酸底物的结合导致 SIRT6 中 NAD ⁺的松散结合。基于这些观察，我们提出了肉豆蔻酸合理的变构结合模式，该模式可以通过稳定NAD ⁺与His131以及乙酰化底物的结合来增强SIRT6的催化活性。此外，我们的分子动力学模拟表明，合成的 SIRT6 激活剂（例如 UBCS039、MDL-801 和 12q）可阻止 NAD ⁺中核糖的翻转，因此可以以类似于脂肪酸的方式稳定底物 -NAD ⁺ -His131 相互作用。总之，我们新提出的 SIRT6 激活机制强调了蛋白质-底物相互作用的重要性，这将有助于新 SIRT6 激活剂的合理设计。

"点击查看英文标题和摘要"

Deciphering the Allosteric Activation Mechanism of SIRT6 Using Molecular Dynamics Simulations

As a member of the histone deacetylase protein family, the NAD⁺-dependent SIRT6 plays an important role in maintaining genomic stability and regulating cell metabolism. Interestingly, SIRT6 has been found to have a preference for hydrolyzing long-chain fatty acyls relative to deacetylation, and it can be activated by fatty acids. However, the mechanisms by which SIRT6 recognizes different substrates and can be activated by small molecular activators are still not well understood. In this study, we carried out extensive molecular dynamic simulations to shed light on these mechanisms. Our results revealed that the binding of the myristoylated substrate stabilizes the catalytically favorable conformation of NAD⁺, while the binding of the acetyl-lysine substrate leads to a loose binding of NAD⁺ in SIRT6. Based on these observations, we proposed a reasonable allosteric binding mode for myristic acid, which can enhance the catalytic activity of SIRT6 by stabilizing the binding of NAD⁺ with His131 as well as the acetylated substrate. Furthermore, our molecular dynamics simulations demonstrated that synthetic SIRT6 activators, such as UBCS039, MDL-801, and 12q, block the flipping of ribose in NAD⁺ and therefore can stabilize substrate–NAD⁺–His131 interactions in a manner similar to fatty acids. In summary, our newly proposed activation mechanism of SIRT6 highlights the importance of protein–substrate interactions, which would facilitate the rational design of new SIRT6 activators.

更新日期：2023-08-31

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南