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

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.
 [1] ;  [2] ;  [3] ;  [3] ;  [4] ;  [1] ;  [5]
  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.
Publication Date:
OSTI Identifier:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
Acta Crystallographica. Section F, Structural biology Communications
Additional Journal Information:
Journal Volume: 71; Journal Issue: 5; Journal ID: ISSN 2053-230X
International Union of Crystallography
Research Org:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases
Country of Publication:
United States
60 APPLIED LIFE SCIENCES Cryptosporidium; inosine 5′-monophosphate dehydrogenase; P131