通过分子建模揭示了PARP1延长反应的机制
Sergey V Pushkarev1, Evgeny M Kirilin2, Vytas K Švedas1,3
1Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119234, Russia.
Biochemistry. Biokhimiia
|September 1, 2024
概括
通过模拟,详细描述了聚ADP-ribose) 聚合酶1 (PARP1) 酶的催化机制. 延长涉及SN1类反应和质子继电系统来激活基质.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 结构生物学 结构生物学
背景情况:
- 聚 ((ADP-ribose) 聚合酶1 (PARP1) 对于DNA修复和转录至关重要.
- PARP1 抑制剂在临床上具有相关性,但其催化机制尚未完全理解.
- PARP1基质和产品的复杂性阻碍了机理学研究.
研究的目的:
- 阐明PARP1-介导的多 ((ADP-ribose) 链延长的详细催化机制.
- 调查PARP1活性部位内的关键氨基酸残留和基质相互作用的作用.
主要方法:
- 用分子建模技术研究PARP1活性部位.
- 使用元动力学模拟来捕捉聚ADP- рибо) 延长的动态过程.
- 分析的重点是反应期间的中间结构和过渡状态.
主要成果:
- 这项研究揭示了SN1类似的SN1机制,用于poly (ADP-ribose) 链延长.
- 在反应过程中确定了一个关键的中间体,即 furanosyl oxocarbenium 离子.
- 接受基质的激活涉及由Glu988和相邻的3'A-OH组介导的质子继电系统.
结论:
- 这些发现为PARP1催化提供了详细的机理洞察.
- 了解这种机制可以为设计更有效的PARP1抑制剂提供信息.
- 鉴定到的质子继电器系统突出了酶催化甘氨酸键形成的新方面.
相关概念视频
01:14Generation of Straight or Branched Actin Filaments
2.9K
The straight or branched structure formation of actin filaments is controlled by nucleating proteins such as the formins and Arp2/3 complex. Formin-mediated assembly results in straight filaments, whereas Arp2/3 protein complex-mediated assembly results in branched actin filaments.
Arp2/3 Complex
Arp2/3 complex is a seven-subunit complex consisting of two proteins similar to actin- Arp2 and Arp3, and five other subunits that help keep Arp2 and Arp3 inactive. When required, the complex is...
Arp2/3 Complex
Arp2/3 complex is a seven-subunit complex consisting of two proteins similar to actin- Arp2 and Arp3, and five other subunits that help keep Arp2 and Arp3 inactive. When required, the complex is...
2.9K
02:37Restarting Stalled Replication Forks
5.8K
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
5.8K
01:02Long-patch Base Excision Repair
7.0K
Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
7.0K
01:31Mechanism of Lamellipodia Formation
2.5K
Cells migrating in response to external stimuli form lamellipodia, which are thin membrane protrusions supported by a mesh of linked, branched, or unbranched actin filaments. These actin filaments interact with myosin motor proteins, creating the dynamic actomyosin complex within the cytoskeleton. Contractility, or the ability to generate contractile stress, is inherent to the actomyosin complex. It helps cells detect the stiffness of the surrounding ECM and exert contractile force for...
2.5K
03:01The Replisome
33.3K
DNA replication is carried out by a large complex of proteins that act in a coordinated matter to achieve high-fidelity DNA replication. Together this complex is known as the DNA replication machinery or the replisome.
The synthesis of the leading and lagging strands is a highly coordinated process. To explain this, the “Trombone model” was proposed by Bruce Alberts in 1980. The DNA loop formation starts when a primer is synthesized on the parent lagging strand. The loop grows with...
The synthesis of the leading and lagging strands is a highly coordinated process. To explain this, the “Trombone model” was proposed by Bruce Alberts in 1980. The DNA loop formation starts when a primer is synthesized on the parent lagging strand. The loop grows with...
33.3K
01:39Mechanism of Filopodia Formation
2.3K
Filopodia are thin, actin-rich cellular protrusions that play an important role in many fundamental cellular functions. They vary in their occurrence, length, and positioning in different cell types, suggesting their diverse roles.
Their main function is to guide migrating cells during normal tissue morphogenesis or cancer metastasis by recognizing and making initial contacts with the extracellular matrix. However, they can also act as stationary cell anchors or help to establish communication...
Their main function is to guide migrating cells during normal tissue morphogenesis or cancer metastasis by recognizing and making initial contacts with the extracellular matrix. However, they can also act as stationary cell anchors or help to establish communication...
2.3K