The gate that governs sulfotransferase selectivity.
The gate that governs sulfotransferase selectivity.
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DOI：
10.1021/bi301492j
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发表时间：
2013-01-15
期刊：
影响因子：
2.9
通讯作者：
Leyh TS
中科院分区：
文献类型：
--
作者：
Cook I;Wang T;Almo SC;Kim J;Falany CN;Leyh TS
人的胞浆硫转移酶(Sults)将硫酰基部分(-SO3)从活化的硫酸盐(3‘-磷酸腺苷-5’-磷酸盐，PAPS)转移到许多代谢物、药物和外源物质的羟基和伯胺上。硫基的接收通常会从根本上改变受体与目标的相互作用。这些酶如何从复杂的胞浆中的数百种候选底物中选择特定的底物仍然是一个重要的问题。最近的工作揭示了PAPS结合导致SULT2A1经历异构化，通过限制受体进入活性位点所必须通过的开口来控制选择性。该酶通过与核苷酸结合的开放状态和闭合状态之间的异构化来保持对大底物的亲和力。在这里，核苷酸诱导关闭的分子基础是在平衡和非平衡分子动力学模拟中探索的。模拟预测，活性部位“帽”，包括核苷酸和受体结合位点，打开和关闭的反应核苷酸。帽子分为核苷酸和受体两部分，它们的运动相互耦合，表现出一种独立性，可以解释异构化。活性部位的帽和碱基之间的静电相互作用的电子内减弱导致帽的受体半部分打开和关闭，而核苷酸盖保持关闭。模拟预测，人类肝脏中最丰富的SULT1A1将利用类似的选择机制。这一预测得到了氟维斯特(一种太大的抗雌激素，不能通过闭合的毛孔)和雌二醇(不受闭合的限制)的检验。平衡和稳态前结合研究证实，SULT1A1经历了核苷酸诱导的异构化，控制了底物的选择。
Human cytosolic sulfotransferases (SULTs) transfer the sulfuryl-moiety (-SO3) from activated sulfate (3′-phosphoadenosine 5′-phosphosulfate, PAPS) to the hydroxyls and primary amines of numerous metabolites, drugs and xenobiotics. Receipt of the sulfuryl-group often radically alters acceptor-target interactions. How these enzymes select particular substrates from the hundreds of candidates in a complex cytosol remains an important question. Recent work reveals PAPS binding causes SULT2A1to undergo an isomerization that controls selectivity by constricting the opening through which acceptors must pass to enter the active site. The enzyme maintains an affinity for large substrates by isomerizing between the open and closed states with nucleotide bound. Here, the molecular basis of the nucleotide-induced closure is explored in equilibrium and non-equilibrium molecular dynamics simulations. The simulations predict that the active-site “cap,” which covers both the nucleotide and acceptor binding sites, opens and closes in response to nucleotide. The cap subdivides into nucleotide and acceptor halves whose motions, while coupled, exhibit an independence that can explain the isomerization. In-silico weakening of electrostatic interactions between the cap and base of the active site causes the acceptor-half of the cap to open and close while the nucleotide lid remains shut. Simulations predict that SULT1A1, the most abundant SULT in human liver, will utilize a similar selection mechanism. This prediction is tested using fulvestrant, an antiestrogen too large to pass through the closed pore, and estradiol, which is not restricted by closure. Equilibrium and presteady state binding studies confirm that SULT1A1 undergoes a nucleotide induced isomerzation that controls substrate selection.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
3.9
作者：
FALANY, CN;VAZQUEZ, ME;ROTH, JA
通讯作者：
ROTH, JA
影响因子：
6.4
作者：
Meinl, W;Pabel, U;Glatt, H
通讯作者：
Glatt, H
影响因子：
3.9
作者：
Falany, JL;Pilloff, DE;Falany, CN
通讯作者：
Falany, CN
人硫代转移酶1a1的广泛底物特异性的分子基础。
影响因子：
3.7
作者：
Berger I;Guttman C;Amar D;Zarivach R;Aharoni A
通讯作者：
Aharoni A