Crystal structures of Saccharomyces cerevisiae tryptophanyl-tRNA synthetase: new insights into the mechanism of tryptophan activation and implications for anti-fungal drug design
Crystal structures of Saccharomyces cerevisiae tryptophanyl-tRNA synthetase: new insights into the mechanism of tryptophan activation and implications for anti-fungal drug design
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酿酒酵母色氨酸-tRNA合成酶的晶体结构：色氨酸激活机制的新见解及其对抗真菌药物设计的影响
DOI：
10.1093/nar/gkp1254
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发表时间：
2010-01
影响因子：
14.9
通讯作者：
Zhou, Minyun
中科院分区：
文献类型：
--
作者：
Shen, Ning;Dong, Xianchi;Zhong, Chen;Ding, Jianping;Zhou, Minyun
氨酰-tRNA 合成酶对氨基酸的特异性激活对于维持翻译保真度至关重要。在这里，我们展示了 apo 形式的酿酒酵母色氨酸-tRNA 合成酶 (sTrpRS) 以及与各种配体形成的复合物的晶体结构。在每个复合物中，活性位点结合有一个硫酸根离子，在色氨酸激活过程中模拟 ATP 的 α- 或 β-磷酸基团。特别是，在 sTrpRS-TrpNH2O 复合物的一个单体中，硫酸根离子似乎在 ATP 向色氨酸移动过程中捕获了 ATP 的 α-磷酸盐的快照。对人类TrpRS-Trp-ATP模型的模拟研究表明，在催化过程中，ATP的α-磷酸被驱动到相当于硫酸根离子的中间位置，然后进一步移动，最终在距亲核试剂约2 Å处波动。保守的精氨酸可能与过渡态易裂键中的氧相互作用，表明其在亲核取代中的关键作用。总而言之，真核 TrpRS 可能采用色氨酸激活的缔合机制，这与细菌 TrpRS 提出的解离机制相反。此外，apo sTrpRS 的结构分析揭示了真菌 TrpRS 的独特特征，可用于合理的抗真菌药物设计。
Specific activation of amino acids by aminoacyl-tRNA synthetases is essential for maintaining translational fidelity. Here, we present crystal structures of Saccharomyces cerevisiae tryptophanyl-tRNA synthetase (sTrpRS) in apo form and in complexes with various ligands. In each complex, there is a sulfate ion bound at the active site which mimics the α- or β-phosphate group of ATP during tryptophan activation. In particular, in one monomer of the sTrpRS–TrpNH2O complex, the sulfate ion appears to capture a snapshot of the α-phosphate of ATP during its movement towards tryptophan. Simulation study of a human TrpRS–Trp–ATP model shows that during the catalytic process the α-phosphate of ATP is driven to an intermediate position equivalent to that of the sulfate ion, then moves further and eventually fluctuates at around 2 Å from the nucleophile. A conserved Arg may interact with the oxygen in the scissile bond at the transition state, indicating its critical role in the nucleophilic substitution. Taken together, eukaryotic TrpRSs may adopt an associative mechanism for tryptophan activation in contrast to a dissociative mechanism proposed for bacterial TrpRSs. In addition, structural analysis of the apo sTrpRS reveals a unique feature of fungal TrpRSs, which could be exploited in rational antifungal drug design.
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影响因子：
5.8
作者：
Gouet, P;Courcelle, E;Métoz, F
通讯作者：
Métoz, F
影响因子：
5.7
作者：
Kapustina, Maryna;Weinreb, Violetta;Carter, Charles W., Jr.
通讯作者：
Carter, Charles W., Jr.
影响因子：
3
作者：
Oostenbrink, C;Villa, A;Van Gunsteren, WF
通讯作者：
Van Gunsteren, WF
DOI：
10.1107/s1600536804016630
发表时间：
2004-08
影响因子：
0.9
作者：
K. Rajagopal;R. D. Franklin;R.V. Krishnakumar;K. Ravikumar;S. Natarajan
通讯作者：
K. Rajagopal;R. D. Franklin;R.V. Krishnakumar;K. Ravikumar;S. Natarajan
影响因子：
2.9
作者：
HERMANS, J;BERENDSEN, HJC;POSTMA, JPM
通讯作者：
POSTMA, JPM