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Structure of Cryptosporidium IMP dehydrogenase bound to an inhibitor with in vivo antiparasitic activity
Author(s) -
Kim Youngchang,
MakowskaGrzyska Magdalena,
Gorla Suresh Kumar,
Gollapalli Deviprasad R.,
Cuny Gregory D.,
Joachimiak Andrzej,
Hedstrom Lizbeth
Publication year - 2015
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.572
H-Index - 37
ISSN - 2053-230X
DOI - 10.1107/s2053230x15000187
Subject(s) - cryptosporidium parvum , imp dehydrogenase , antiparasitic , in vivo , stereochemistry , chemistry , inosine , antiparasitic agent , hypoxanthine , biochemistry , inosine monophosphate , enzyme , biology , pharmacology , microbiology and biotechnology , nucleotide , medicine , surgery , gene , transplantation , mycophenolic acid , pathology
Inosine 5′‐monophosphate dehydrogenase (IMPDH) is a promising target for the treatment of Cryptosporidium infections. Here, the structure of C. parvum IMPDH ( Cp IMPDH) 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 NO 2 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.