SIRT3、SIRT5催化长链脂肪酸修饰或琥珀酸修饰蛋白去酰化的机制研究
发布时间：2018-11-07 15:44
【摘要】：Sirtuins在许多生物过程以及老龄化疾病中起重要作用,它们除了可以催化去乙酰化反应,还可以催化例如去琥珀酰化、去长链脂肪酸酰化等反应。在第一部分工作中,为了研究sirtuins去长链脂肪酸酰化的分子机制,我们解析了SIRT3蛋白与肉豆蔻酰化、棕榈酰化的H3K9多肽的复合物晶体结构,我们发现:肉豆蔻酰、棕榈酰基团结合在SIRT3蛋白C口袋内的不同位置;随着底物的不同,C口袋也随之发生改变。Sirtuin蛋白C口袋的可塑性可以帮助我们设计sirtuins的抑制剂,也有助于阐释sirtuins去长链脂肪酸的分子机制。Sirtuins抑制剂可作为分子探针用来研究sirtuins的生物功能,并且可作为潜在的老龄化疾病的治疗药物。到目前为止,许多抑制剂结合在sirtuins的A、B、C口袋。为设计SIRT5抑制剂,在第二部分工作中,我们解析了SIRT5蛋白与带香豆素标记的琥珀酰化底物多肽ac-LGKsuc-AMC的复合物晶体结构。通过比较“SIRT5/ac-LGKsuc-AMC”、“SIRT5/H3K9suc”(SIRT5与不带香豆素标记的琥珀酰化H3K9多肽)复合物结构,我们发现,由于香豆素所形成的空间位阻,SIRT5蛋白的250-257位氨基酸发生了较大的构象变化。Ser251、Ser252、Val253会向Rossmann折叠移动,因此荧光团分子香豆素(AMC)扩大了蛋白催化区域的狭缝,该结构可帮助我们设计小分子化合物来调节SIRT5的功能。另外,我们发现白藜芦醇的衍生物白皮杉醇是SIRT5蛋白的抑制剂。基于蛋白热稳定性实验和圆二色谱实验结果,我们提出白皮杉醇抑制SIRT5去琥珀酰化的一种机制,即白皮杉醇结合SIRT5、使得SIRT5处于一种相对稳定的构象,而SIRT5在催化反应过程中要经历一系列构象变化,这种稳定的构象不利于SIRT5的催化反应。我们还需进一步研究白皮杉醇与SIRT5的具体结合模式,来确定白皮杉醇抑制SIRT5酶活的作用机理。
[Abstract]:Sirtuins play an important role in many biological processes, as well as in the aging of the disease, which, in addition to the catalytic deacetylation reaction, can also catalyze the reaction of, for example, desulphation, long-chain fatty acid precipitation, and the like. In the first part, in order to study the molecular mechanism of sirtuins to long-chain fatty acid precipitation, we analyzed the crystal structure of the complex of the SIRT3 protein and the deregulated, palm-encapsulated H3K9 polypeptide. We found that: Carnauba-based groups bind to different positions in the pocket of the SIRT3 protein C; as the substrate is different, the C-pocket also changes. The plasticity of the Siruin protein C pocket can help us to design inhibitors of sirtuins and help to explain the molecular mechanism of sirtuins to long-chain fatty acids. the sirtuins inhibitor can be used as a molecular probe to study the biological function of sirtuins and can be used as a therapeutic agent for potential aging diseases. So far, many inhibitors bind to the A, B, and C pockets of sirtuins. To design the SIRT5 inhibitor, in the second part, we resolved the complex crystal structure of the SIRT5 protein and the coumarin-labeled amber-encapsulated substrate polypeptide ac-LGKsuc-AMC. By comparing the structure of the 鈥淪IRT5/ ac-LGKsuc-AMC鈥，
本文编号：2316815
[Abstract]:Sirtuins play an important role in many biological processes, as well as in the aging of the disease, which, in addition to the catalytic deacetylation reaction, can also catalyze the reaction of, for example, desulphation, long-chain fatty acid precipitation, and the like. In the first part, in order to study the molecular mechanism of sirtuins to long-chain fatty acid precipitation, we analyzed the crystal structure of the complex of the SIRT3 protein and the deregulated, palm-encapsulated H3K9 polypeptide. We found that: Carnauba-based groups bind to different positions in the pocket of the SIRT3 protein C; as the substrate is different, the C-pocket also changes. The plasticity of the Siruin protein C pocket can help us to design inhibitors of sirtuins and help to explain the molecular mechanism of sirtuins to long-chain fatty acids. the sirtuins inhibitor can be used as a molecular probe to study the biological function of sirtuins and can be used as a therapeutic agent for potential aging diseases. So far, many inhibitors bind to the A, B, and C pockets of sirtuins. To design the SIRT5 inhibitor, in the second part, we resolved the complex crystal structure of the SIRT5 protein and the coumarin-labeled amber-encapsulated substrate polypeptide ac-LGKsuc-AMC. By comparing the structure of the 鈥淪IRT5/ ac-LGKsuc-AMC鈥，
本文编号：2316815
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