Kim Youngchang, Makowska-Grzyska Magdalena, Gorla Suresh Kumar, Gollapalli Deviprasad R, Cuny Gregory D, Joachimiak Andrzej, Hedstrom Lizbeth
Center for Structural Genomics of Infectious Diseases, Computational Institute, University of Chicago, 5735 S. Ellis Avenue, Chicago, IL 60637, USA.
Department of Biology, Brandeis University, 415 South Street, Waltham, MA 02454, USA.
Acta Crystallogr F Struct Biol Commun. 2015 May;71(Pt 5):531-8. doi: 10.1107/S2053230X15000187. Epub 2015 Apr 21.
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.
肌苷5'-单磷酸脱氢酶（IMPDH）是治疗隐孢子虫感染的一个有前景的靶点。在此，报道了微小隐孢子虫IMPDH（CpIMPDH）与肌苷5'-单磷酸（IMP）以及具有体内抗隐孢子虫活性的抑制剂P131形成的复合物的结构。P131含有两个芳香基团，其中一个与IMP的次黄嘌呤环相互作用，而另一个与相邻亚基中酪氨酸的芳香环相互作用。此外，胺基和NO2基团结合在水合腔中，与蛋白质形成水介导的氢键。设计取代这些水分子的化合物是进一步优化用于抗寄生虫和抗菌应用的微小隐孢子虫抑制剂的新策略。
