title: 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.
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Computational Institute, University of Chicago, 5735 S. Ellis Avenue, Chicago, IL 60637, USA.
authors.forename: Youngchang
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Computational Institute, University of Chicago, 5735 S. Ellis Avenue, Chicago, IL 60637, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Makowska-Grzyska
authors.affiliation: Department of Biology, Brandeis University, 415 South Street, Waltham, MA 02454, USA.
authors.forename: Suresh Kumar
authors.initials: SK
authors.lastname: Gorla
authors.affiliation: Department of Biology, Brandeis University, 415 South Street, Waltham, MA 02454, USA.
authors.forename: Deviprasad R
authors.initials: DR
authors.lastname: Gollapalli
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Science and Research Building 2, Houston, TX 77204, USA.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cuny
authors.affiliation: Center for Structural Genomics of Infectious Diseases, Computational Institute, University of Chicago, 5735 S. Ellis Avenue, Chicago, IL 60637, USA.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Joachimiak
authors.affiliation: Department of Biology, Brandeis University, 415 South Street, Waltham, MA 02454, USA.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
mesh_terms: D000595:Amino Acid Sequence; D000977:Antiparasitic Agents / Q000737:chemistry* / Q000378:metabolism; D003458:Cryptosporidium / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D007168:IMP Dehydrogenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D000977:Antiparasitic Agents; D004791:Enzyme Inhibitors; D007168:IMP Dehydrogenase
keywords: Cryptosporidium; P131; inosine 5′-monophosphate dehydrogenase