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Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity.

ABSTRACT: 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.

SUBMITTER: Kim Y

PROVIDER: S-EPMC4427161 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity.

Kim Youngchang Y Makowska-Grzyska Magdalena M Gorla Suresh Kumar SK Gollapalli Deviprasad R DR Cuny Gregory D GD Joachimiak Andrzej A Hedstrom Lizbeth L

Acta crystallographica. Section F, Structural biology communications 20150421 Pt 5

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 an ...[more]

PMID: 25945705

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The structural basis of Cryptosporidium -specific IMP dehydrogenase inhibitor selectivity.

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