Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity.
Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity.
复制标题
隐孢子虫脱氢酶与抑制剂具有体内抗寄生虫活性的结构。
DOI：
10.1107/s2053230x15000187
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Hedstrom L
中科院分区：
文献类型：
--
作者：
Kim Y;Makowska-Grzyska M;Gorla SK;Gollapalli DR;Cuny GD;Joachimiak A;Hedstrom L
Compound P131 displays antiparasitic activity in a mouse model of Cryptosporidium infection, validating IMP dehydrogenase (IMPDH) as a drug target. Here, the structure of the enzyme–substrate–P131 complex is reported at 2.05 Å resolution. The structure is an important step to further refine the design of IMPDH inhibitors. Inosine 5′-monophosphate dehydrogenase (IMPDH) is a promising target for the treatment of Cryptosporidium infections. Here, the structure of C. parvum IMPDH (CpIMPDH) in complex with inosine 5′-monophosphate (IMP) and P131, an inhibitor with in vivo anticryptosporidial activity, is reported. P131 contains two aromatic groups, one of which interacts with the hypoxanthine ring of IMP, while the second interacts with the aromatic ring of a tyrosine in the adjacent subunit. In addition, the amine and NO2 moieties bind in hydrated cavities, forming water-mediated hydrogen bonds to the protein. The design of compounds to replace these water molecules is a new strategy for the further optimization of C. parvum inhibitors for both antiparasitic and antibacterial applications.
