Mechanism of PARP1 Elongation Reaction Revealed by Molecular Modeling

IF 2.3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sergey V. Pushkarev, Evgeny M. Kirilin, Vytas K. Švedas, Dmitry K. Nilov
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引用次数: 0

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) plays a major role in the DNA damage repair and transcriptional regulation, and is targeted by a number of clinical inhibitors. Despite this, catalytic mechanism of PARP1 remains largely underexplored because of the complex substrate/product structure. Using molecular modeling and metadynamics simulations we have described in detail elongation of poly(ADP-ribose) chain in the PARP1 active site. It was shown that elongation reaction proceeds via the SN1-like mechanism involving formation of the intermediate furanosyl oxocarbenium ion. Intriguingly, nucleophilic 2′A-OH group of the acceptor substrate can be activated by the general base Glu988 not directly but through the proton relay system including the adjacent 3′A-OH group.

Abstract Image

通过分子建模揭示 PARP1 延长反应机制
多聚(ADP-核糖)聚合酶 1(PARP1)在 DNA 损伤修复和转录调控中发挥着重要作用,是许多临床抑制剂的靶向药物。尽管如此,由于底物/产物结构复杂,PARP1 的催化机理在很大程度上仍未得到充分探索。通过分子建模和元动力学模拟,我们详细描述了 PARP1 活性位点中聚(ADP-核糖)链的伸长过程。研究表明,伸长反应是通过类似 SN1 的机制进行的,其中涉及中间体呋喃糖基氧羰基离子的形成。耐人寻味的是,受体底物的亲核 2'A-OH 基团不是直接被一般碱基 Glu988 激活,而是通过质子中继系统(包括邻近的 3'A-OH 基团)激活。
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来源期刊
Biochemistry (Moscow)
Biochemistry (Moscow) 生物-生化与分子生物学
CiteScore
4.70
自引率
3.60%
发文量
139
审稿时长
2 months
期刊介绍: Biochemistry (Moscow) is the journal that includes research papers in all fields of biochemistry as well as biochemical aspects of molecular biology, bioorganic chemistry, microbiology, immunology, physiology, and biomedical sciences. Coverage also extends to new experimental methods in biochemistry, theoretical contributions of biochemical importance, reviews of contemporary biochemical topics, and mini-reviews (News in Biochemistry).
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