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

Journal Article · Tue Apr 21 00:00:00 EDT 2015 · Acta Crystallographica. Section F, Structural Biology Communications

DOI:https://doi.org/10.1107/S2053230X15000187· OSTI ID:1212708

Kim, Youngchang ^[1]; Makowska-Grzyska, Magdalena ^[2]; Gorla, Suresh Kumar ^[3]; Gollapalli, Deviprasad R. ^[3]; Cuny, Gregory D. ^[4]; Joachimiak, Andrzej ^[1]; Hedstrom, Lizbeth ^[5]

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1. Univ. of Chicago, Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases; Argonne National Laboratory, Argonne, IL (United States). Structural Biology Center.
2. Univ. of Chicago, Chicago, IL (United States). Center for Structural Genomics of Infectious Diseases.
3. Brandeis Univ., Waltham, MA (United States). Dept. of Biology.
4. Univ. of Houston, Houston, TX (United States). Dept. of Pharmacological and Pharmaceutical Sciences.
5. Brandeis Univ., Waltham, MA (United States). Depts. of Biology and Chemistry.

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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States)
• Sponsoring Organization: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID)
• Grant/Contract Number: AC02-06CH11357
• OSTI ID: 1212708
• Journal Information: Acta Crystallographica. Section F, Structural Biology Communications, Vol. 71, Issue 5; ISSN 2053-230X
• Publisher: International Union of Crystallography
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
Cryptosporidium
inosine 5′-monophosphate dehydrogenase
P131