Mechanism of allosteric activation of SIRT6 revealed by the action of rationally designed activators.
Mechanism of allosteric activation of SIRT6 revealed by the action of rationally designed activators.
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合理设计的激活剂的作用揭示了 SIRT6 变构激活机制
DOI：
10.1016/j.apsb.2020.09.010
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Lu S;Chen Y;Wei J;Zhao M;Ni D;He X;Zhang J
最近发现的激活剂化合物结合到NAD+依赖性蛋白质赖氨酸脱乙酰酶，sirtuin 6（SIRT 6）上的变构位点引起了人们的兴趣，并提出了一个药物靶点，用于衰老相关的疾病和癌症。然而，激活剂MDL-801变构激活SIRT 6的潜在机制在很大程度上仍然难以捉摸，因为在激活剂结合后没有观察到重大的构象变化。通过将分子动力学模拟与野生型SIRT 6及其变体M136 A的生物化学和动力学分析相结合，我们表明MDL-801的右苯环（R环）上的2-甲基-4-氟-5-溴取代基的构象旋转，揭示了以前未见的疏水相互作用，有助于增加SIRT 6的活化脱乙酰活性。这一假设得到了两种新合成的MDL-801衍生物的进一步支持，这两种衍生物通过去除R环上的5-Br原子（MDL-801-D1）或抑制R环的旋转（MDL-801-D2）而得到。我们进一步提出，5-Br原子作为控制配体变构功效的变构驱动器。我们的研究突出了激活剂结合对变构酶催化活性的影响，并为提高脱乙酰活性提供了合理的途径。Sirtuin 6（SIRT 6）是一种NAD+依赖的赖氨酸脱乙酰酶，是治疗衰老和癌症的药物靶点。通过结合分子动力学模拟、化合物合成、野生型SIRT 6及其变体的生化和动力学分析，我们阐明了小分子化合物对SIRT 6的变构激活机制。
The recent discovery of activator compounds binding to an allosteric site on the NAD+-dependent protein lysine deacetylase, sirtuin 6 (SIRT6) has attracted interest and presents a pharmaceutical target for aging-related and cancer diseases. However, the mechanism underlying allosteric activation of SIRT6 by the activator MDL-801 remains largely elusive because no major conformational changes are observed upon activator binding. By combining molecular dynamics simulations with biochemical and kinetic analyses of wild-type SIRT6 and its variant M136A, we show that conformational rotation of 2-methyl-4-fluoro-5-bromo substituent on the right phenyl ring (R-ring) of MDL-801, which uncovers previously unseen hydrophobic interactions, contributes to increased activating deacetylation activity of SIRT6. This hypothesis is further supported by the two newly synthesized MDL-801 derivatives through the removal of the 5-Br atom on the R-ring (MDL-801-D1) or the restraint of the rotation of the R-ring (MDL-801-D2). We further propose that the 5-Br atom serves as an allosteric driver that controls the ligand allosteric efficacy. Our study highlights the effect of allosteric enzyme catalytic activity by activator binding and provides a rational approach for enhancing deacetylation activity. Sirtuin 6 (SIRT6), a NAD+-dependent protein lysine deacetylase, has attracted interest and presents a pharmaceutical target for aging-related and cancer diseases. By combining molecular dynamics simulations, compound synthesis, and biochemical and kinetic analyses of wild-type SIRT6 and its variants, we elucidate the allosteric activation mechanism of SIRT6 by small-molecule compounds.
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DOI：
10.1039/c8cc02426j
发表时间：
2018-06-19
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Maria-Solano MA ;Serrano-Hervás E ;Romero-Rivera A ;Iglesias-Fernández J ;Osuna S
通讯作者：
Osuna S
深入了解癌蛋白 K-Ras4B 变构激活 PI3K α 的机制
DOI：
10.1016/j.ijbiomac.2019.12.020
发表时间：
2020-02-01
影响因子：
8.2
作者：
Li, Xinyi;Dai, Jinyuan;Lu, Shaoyong
通讯作者：
Lu, Shaoyong
影响因子：
2.9
作者：
Fan Y;Cembran A;Ma S;Gao J
通讯作者：
Gao J
影响因子：
7.3
作者：
Lu, Shaoyong;Zhang, Jian
通讯作者：
Zhang, Jian
影响因子：
6.8
作者：
Guarnera, Enrico;Berezovsky, Igor N.
通讯作者：
Berezovsky, Igor N.