Structural Analysis of Thymidylate Synthase from Kaposi's Sarcoma-Associated Herpesvirus with the Anticancer Drug Raltitrexed.
Structural Analysis of Thymidylate Synthase from Kaposi's Sarcoma-Associated Herpesvirus with the Anticancer Drug Raltitrexed.
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DOI：
10.1371/journal.pone.0168019
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Lee JY
中科院分区：
文献类型：
--
作者：
Choi YM;Yeo HK;Park YW;Lee JY
卡波西肉瘤相关疱疹病毒（Kaposi's sarcoma-associated herpesvirus，KSHV）是一种高度传染性的人类疱疹病毒，可导致卡波西肉瘤。KSHV编码功能性胸苷酸合酶，其是抗癌药物如雷替曲塞或5-氟尿嘧啶的靶标。胸苷酸合成酶以5，10-亚甲基四氢叶酸（mTHF）为共底物，催化2′-脱氧尿苷-5 ′-单磷酸（dUMP）转化为胸苷-5 ′-单磷酸（dTMP）。分别在1.7 nm、2.0 nm和2.4 nm处测定了来自KSHV（载脂蛋白）的胸苷酸合酶、与dUMP的复合物（二元）以及与dUMP和雷替曲塞的复合物（三元）的晶体结构。人胸苷酸合成酶与大肠杆菌的三元复合物结构。大肠杆菌胸苷酸合成酶为封闭构象，而KSHV胸苷酸合成酶为开放构象，与大鼠胸苷酸合成酶相似。与人胸苷酸合成酶不同，KSHV胸苷酸合成酶的复杂结构在Cys 219的巯基和dUMP的C6原子之间没有共价键。催化Cys残基在载脂蛋白结构中表现出双重构象，并且其巯基在络合物结构中配体结合时朝向dUMP的C6原子而没有共价键。这些结构数据提供了抗叶酸剂如雷替曲塞作为病毒诱导的抗癌药物的潜在用途，以及设计靶向KSHV胸苷酸合酶的药物的结构基础。
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a highly infectious human herpesvirus that causes Kaposi’s sarcoma. KSHV encodes functional thymidylate synthase, which is a target for anticancer drugs such as raltitrexed or 5-fluorouracil. Thymidylate synthase catalyzes the conversion of 2′-deoxyuridine-5′-monophosphate (dUMP) to thymidine-5′-monophosphate (dTMP) using 5,10-methylenetetrahydrofolate (mTHF) as a co-substrate. The crystal structures of thymidylate synthase from KSHV (apo), complexes with dUMP (binary), and complexes with both dUMP and raltitrexed (ternary) were determined at 1.7 Å, 2.0 Å, and 2.4 Å, respectively. While the ternary complex structures of human thymidylate synthase and E. coli thymidylate synthase had a closed conformation, the ternary complex structure of KSHV thymidylate synthase was observed in an open conformation, similar to that of rat thymidylate synthase. The complex structures of KSHV thymidylate synthase did not have a covalent bond between the sulfhydryl group of Cys219 and C6 atom of dUMP, unlike the human thymidylate synthase. The catalytic Cys residue demonstrated a dual conformation in the apo structure, and its sulfhydryl group was oriented toward the C6 atom of dUMP with no covalent bond upon ligand binding in the complex structures. These structural data provide the potential use of antifolates such as raltitrexed as a viral induced anticancer drug and structural basis to design drugs for targeting the thymidylate synthase of KSHV.
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