Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed
Structural analysis of a shrimp thymidylate synthase reveals species-specific interactions with dUMP and raltitrexed
复制标题
虾胸苷酸合酶的结构分析揭示了 dUMP 和雷替曲塞的物种特异性相互作用
DOI：
10.1007/s00343-019-9184-8
复制
发表时间：
2020-02
影响因子：
1.6
通讯作者：
Qingjun Ma
中科院分区：
文献类型：
--
作者：
Changshui Liu;Kun Zang;Shihao Li;Fuhua Li;Qingjun Ma
胸苷酸合酶（TS）是胸苷单磷酸盐从头生物合成的关键酶，是针对癌症和感染性疾病的化学疗法的众所周知的药物靶标。除临床价值外，TS应该是Promisi
Thymidylate synthase (TS) is a key enzyme in the de novo biosynthesis of thymidine monophosphate, serving as a well-known drug target in chemotherapy against cancers and infectious diseases. Additional to its clinical value, TS is supposed to be a promising drug target in aquatic-disease control. To facilitate designing pathogen-specific TS inhibitors for shrimp-disease control, we report the crystal structures of TS fromLitopenaeus vannamei(LvTS) in the apo form, LvTS-dUMP complex and LvTS-dUMP-raltitrexed complex at 2.27 Å, 1.54 Å, and 1.56 Å resolution, respectively. LvTS shares a similar fold with known TSs, existing as a dimer in the crystal. The apo LvTS and LvTS-dUMP take an open conformation, and raltitrexed binding induces structural changes into a closed conformation in LvTS-dUMP-raltitrexed. Compared to those in other known TS-dUMP-raltitrexed complexes with the closed conformation, the C-terminal loop in LvTS-dUMP-raltitrexed shifts its position away from the bound raltitrexed; the distance between C6 of dUMP and Sγ of the catalytic cysteine is obviously longer than that in the known TS structures with closed conformations, resembling that in the TS structures with open conformations. Other species-specific interactions with dUMP and raltitrexed are also observed. Therefore, LvTS-dUMP-raltitrexed adopts a loosely closed conformation with structural features intermediate between the closed and the open conformations that were reported in other TSs. Our study provides the first crustcean TS structure, and reveals species-specific interactions between TSs and the ligands, which would facilitate designing pathogen-specific TS inhibitors for shrimp-disease control.
登录
查看更多内容
影响因子：
14.9
作者：
ASLANIDIS, C;DEJONG, PJ
通讯作者：
DEJONG, PJ
DOI：
10.1007/978-1-59259-725-3
发表时间：
1999
期刊：
--
影响因子：
--
作者：
A. Jackman
通讯作者：
A. Jackman
影响因子：
5.8
作者：
E. De Clercq;J. Balzarini;J. Descamps;C. Bigge;C. Chang;P. Kalaritis;M. Mertes
通讯作者：
E. De Clercq;J. Balzarini;J. Descamps;C. Bigge;C. Chang;P. Kalaritis;M. Mertes
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
3.7
作者：
Choi YM;Yeo HK;Park YW;Lee JY
通讯作者：
Lee JY