Two crystal structures of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveal protein-ligand interactions including a structural basis for observed antifolate resistance
Two crystal structures of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveal protein-ligand interactions including a structural basis for observed antifolate resistance
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DOI：
10.1107/s1744309105002435
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发表时间：
2005-03-01
影响因子：
0.9
通讯作者：
Anderson, AC
中科院分区：
文献类型：
--
作者：
Anderson, AC
人隐孢子虫是一种原生动物寄生虫，可导致急性胃肠道疾病。目前还没有治疗隐孢子虫病的有效方法，这突显了发现新药的必要性。通过对人绒毛虫二氢叶酸还原酶-胸苷合成酶(DHFR-TS)在2.8和2.87埃分辨率下两种晶体结构中蛋白质-配体相互作用的分析，揭示了人绒毛虫DHFR活性部位Ile29、Thr58和Cys113残基的相互作用为观察到的抗叶酸抗性提供了可能的结构基础。与人DHFR结构的比较揭示了活性部位的差异，这可能被用来设计物种选择性抑制剂。
Cryptosporidium hominis is a protozoan parasite that causes acute gastrointestinal illness. There are no effective therapies for cryptosporidiosis, highlighting the need for new drug-lead discovery. An analysis of the protein-ligand interactions in two crystal structures of dihydrofolate reductase-thymidylate synthase (DHFR-TS) from C. hominis, determined at 2.8 and 2.87 angstrom resolution, reveals that the interactions of residues Ile29, Thr58 and Cys113 in the active site of C. hominis DHFR provide a possible structural basis for the observed antifolate resistance. A comparison with the structure of human DHFR reveals active-site differences that may be exploited for the design of species-selective inhibitors.