Skip Navigation

Structural Genomics Centers for Infectious Diseases

Skip Content Marketing
  • Share this:
  • submit to facebook
  • Tweet it
  • submit to reddit
  • submit to StumbleUpon
  • submit to Google +

Featured Structure: Cryptosporidium parvum IMPDH

The parasite Cryptosporidium parvum is a major cause of diarrhea and malnutrition in the developing world. This disease may be prolonged and life-threatening in immune-compromised patients. Currently, no effective therapy exists for C. parvum infections. The parasite relies on inosine 5’-monophosphate dehydrogenase (IMPDH) to obtain guanine nucleotides, one of the building blocks of DNA. The parasitic enzyme (CpIMPDH) is structurally distinct from mammalian IMPDHs and is an attractive target for the development of new therapeutics.

A high-throughput screening effort identified structurally diverse, selective CpIMPDH inhibitors. Several of these compounds have been optimized to produce nanomolar inhibitors. A team of researchers, from the Center for Structural Genomics of Infectious Diseases, Brandeis University, the University of Georgia, Harvard Medical School and the University of Houston, determined the structure of CpIMPDH, in complex with its substrate, inosine 5’-monophosphate (IMP), and one optimized inhibitor, a benzoxazole-based compound Q21 (PDB id: 4IXH).

The determined structure provides a more complete understanding of IMPDH activity. For example, researchers found that the tetrameric CpIMPDH binds one molecule of inhibitor per monomer (see Figure, panel A). The inhibitor binds where two adjacent monomers meet (see Figure, panel B). This improved understanding of IMPDH activity helps researchers determine how and where inhibitor molecules bind, aiding therapeutic drug optimization.

Complex of CpIMPDH with its substrate, IMP and an inhibitor, Q21. (A). Tetramer of the CpIMPDH. Each monomer is colored differently. (B). CpIMPDH active site with IMP (gray) Q21 (magenta) and the interacting residues (M308, E329, A164, L170, S354’ and Y358’) from CpIMPDH shown in a stick representation. A water molecule is shown as a red sphere and hydrogen bonding interactions are shown as blue dashed lines. A prime indicates a residue from the adjacent monomer.

Complex of CpIMPDH with its substrate, IMP and an inhibitor, Q21. (A). Tetramer of the CpIMPDH. Each monomer is colored differently. (B). CpIMPDH active site with IMP (gray) Q21 (magenta) and the interacting residues (M308, E329, A164, L170, S354’ and Y358’) from CpIMPDH shown in a stick representation. A water molecule is shown as a red sphere and hydrogen bonding interactions are shown as blue dashed lines. A prime indicates a residue from the adjacent monomer.

Reference

Optimization of Benzoxazole-Based Inhibitors of Cryptosporidium parvum Inosine 5'-Monophosphate Dehydrogenase. Gorla SK, Kavitha M, Zhang M, Chin JE, Liu X, Striepen B, Makowska-Grzyska M, Kim Y, Joachimiak A, Hedstrom L, Cuny GD. J. Med Chem. 2013 56(10):4028-43. PubMed PMID: 23668331

Related Link

Last Updated July 26, 2013