The structural basis of ATP as an allosteric modulator.
The structural basis of ATP as an allosteric modulator.
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DOI：
10.1371/journal.pcbi.1003831
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发表时间：
2014-09
影响因子：
4.3
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Lu S;Huang W;Wang Q;Shen Q;Li S;Nussinov R;Zhang J
腺苷-5 ' -三磷酸（ATP）通常被认为是能量流通和蛋白质修饰的底物。最近的研究揭示了ATP在细胞信号转导中的变构功能，但对ATP的这一关键行为知之甚少。通过对溶液和蛋白质中ATP的广泛分析，我们发现游离ATP在溶液中可以以紧凑和扩展的构象存在，这两种不同的构象特征可能是ATP发挥不同生物学功能的原因：ATP分子在变构结合位点上既采用紧凑构象，又采用扩展构象，而在底物结合位点上则保留扩展构象。轻推弹性带模拟揭示了ATP与尿苷单磷酸激酶相应的变构位点和底物结合位点结合的不同动态过程，并表明在溶液中ATP优先与蛋白质的底物结合位点结合。当ATP分子占据变构结合位点时，ATP的变构触发主要来自ATP的三磷酸部分，少部分来自ATP的腺嘌呤部分。综上所述，我们的结果提供了对生物系统中负责调节的ATP变构功能的全面理解。内源性ATP可以看作是细胞信号转导的底物和变构调节剂。我们分析了变构atp结合位点和底物atp结合位点的性质，发现变构atp结合位点比底物atp结合位点更保守。变构ATP分子在变构结合位点上采用紧密型和扩展型构象，而底物ATP分子在底物结合位点上采用扩展型构象。这两种不同的构象特征可能是ATP在细胞信号传导中发挥不同生物学功能的原因。此外，据我们所知，这项研究阐明了ATP进入相应的变构和底物ATP结合位点的第一次全面的原子水平研究。特别地，ATP的腺嘌呤和三磷酸部分都可能是一个变构触发，将信号从变构传播到功能位点。本研究提供的详细机制可能适用于其他酶与变构或底物ATP分子的复合物，并为ATP在细胞信号传导中作为底物和变构调节剂的分子基础提供重要见解。
Adenosine-5’-triphosphate (ATP) is generally regarded as a substrate for energy currency and protein modification. Recent findings uncovered the allosteric function of ATP in cellular signal transduction but little is understood about this critical behavior of ATP. Through extensive analysis of ATP in solution and proteins, we found that the free ATP can exist in the compact and extended conformations in solution, and the two different conformational characteristics may be responsible for ATP to exert distinct biological functions: ATP molecules adopt both compact and extended conformations in the allosteric binding sites but conserve extended conformations in the substrate binding sites. Nudged elastic band simulations unveiled the distinct dynamic processes of ATP binding to the corresponding allosteric and substrate binding sites of uridine monophosphate kinase, and suggested that in solution ATP preferentially binds to the substrate binding sites of proteins. When the ATP molecules occupy the allosteric binding sites, the allosteric trigger from ATP to fuel allosteric communication between allosteric and functional sites is stemmed mainly from the triphosphate part of ATP, with a small number from the adenine part of ATP. Taken together, our results provide overall understanding of ATP allosteric functions responsible for regulation in biological systems. The endogenous ATP can be regarded as a substrate and an allosteric modulator in cellular signal transduction. We analyzed the properties of allosteric and substrate ATP-binding sites and found that the allosteric ATP-binding sites are less conserved than the substrate ATP-binding sites. Allosteric ATP molecules adopt both compact and extended conformations in the allosteric binding sites, while substrate ATP molecules adopt extended conformations in the substrate binding sites. The two different conformational characteristics may be responsible for ATP to exert distinct biological functions in cell signaling. In addition, to our knowledge, this study illuminates the first comprehensive atomic level investigations of ATP access to the corresponding allosteric and substrate ATP-binding sites. Specially, both the adenine and triphosphate parts of ATP could be an allosteric trigger to propagate the signal from the allosteric to functional sites. The detailed mechanism presented in this study may apply to other enzymes in complex with allosteric or substrate ATP molecules, and provide important insights for the molecular basis of ATP acting as a substrate and an allosteric modulator in cell signaling.
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影响因子：
2.2
作者：
Bergonzo, Christina;Campbell, Arthur J.;Walker, Ross C.;Simmerling, Carlos
通讯作者：
Simmerling, Carlos
影响因子：
3.7
作者：
Huang M;Lu S;Shi T;Zhao Y;Chen Y;Li X;Liu X;Huang Z;Zhang J
通讯作者：
Zhang J
DOI：
10.1073/pnas.89.22.10915
发表时间：
1992-11-15
影响因子：
11.1
作者：
HENIKOFF, S;HENIKOFF, JG
通讯作者：
HENIKOFF, JG
星形胶质细胞衍生的 ATP 调节抑郁样行为
影响因子：
82.9
作者：
Cao, Xiong;Li, Liang-Ping;Gao, Tian-Ming
通讯作者：
Gao, Tian-Ming
影响因子：
11.4
作者：
Hubbard, SR
通讯作者：
Hubbard, SR