Tritrichomonas foetus: a strategy for structure-based inhibitor design of a protozoan inosine-5'-monophosphate dehydrogenase.
Inosine-5'-monophosphate dehydrogenase (IMPDH) is an attractive drug target for the control of parasitic infections. The enzyme catalyzes the NAD-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the committed step in guanosine monophosphate (GMP) biosynthesis. We have determined the crystal structures of IMPDH from the protozoan parasite Tritrichomonas foetus in the apo form at 2.3 A resolution and the enzyme-XMP complex at 2.6 A resolution. The enzyme forms a cyclic (C4) homotetramer. The core domain of each monomer forms an eight-stranded parallel beta/alpha barrel with the enzyme active site at the C-termini of the barrel beta strands which lies near the center of the fourfold axis of the tetramer. While the electron-density for XMP in the complex structure is well-defined, the NAD cofactor and a nearby loop containing the catalytic cysteine (Cys-319) are disordered. This disorder at the active site suggests that a high degree of flexibility may be inherent to the catalytic function of IMPDH, making this area a difficult target for structure-based inhibitor design. Unlike IMPDHs from other species, the T. foetus enzyme coordinates the substrate phosphate with a single arginine guanidinium in the active site. Furthermore, a deep groove extends 8 A from the substrate phosphate away from the sugar. This structural uniqueness forms the basis of our efforts to design compounds that specifically inhibit the parasite enzyme.
Luecke
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Department of Molecular Biology and Biochemistry, University of California, Irvine 92697, USA. hudel@uci.edu
Prosise
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Whitby
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D000818:Animals; D000981:Antiprotozoal Agents; D001665:Binding Sites; D003198:Computer Simulation; D003461:Crystallography; D015195:Drug Design; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D011487:Protein Conformation; D012107:Research Design; D012265:Ribonucleotides / Q000737:chemistry; D016835:Tritrichomonas foetus / Q000201:enzymology*; D019820:Xanthine
D000981:Antiprotozoal Agents; D012265:Ribonucleotides; D019820:Xanthine; C011141:xanthosine monophosphate; D007168:IMP Dehydrogenase