A 1.4 Å Crystal Structure for the Hypoxanthine Phosphoribosyltransferase of Trypanosoma cruzi,
- 1 October 1998
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 37 (43), 15066-15075
- https://doi.org/10.1021/bi981052s
Abstract
The hypoxanthine phosphoribosyltransferase (HPRT) from Trypanosoma cruzi, etiologic agent of Chagas' disease, was cocrystallized with the inosine analogue Formycin B (FmB) and the structure determined to 1.4 Å resolution. This is the highest resolution structure yet reported for a phosphoribosyltransferase (PRT), and the asymmetric unit of the crystal contains a dimer of closely associated, nearly identical subunits. A conserved nonproline cis peptide in one active-site loop exposes the main-chain nitrogen to the enzyme active site, while the adjacent lysine side chain interacts with the other subunit of the dimer, thereby providing a possible mechanism for communication between the subunits and their active sites. The three-dimensional coordinates for the invariant Ser103−Tyr104 dipeptide are reported here for the first time. These are the only highly conserved residues in a second active-site loop, termed the long flexible loop, which is predicted to close over the active site of HPRTs to protect a labile transition state [Eads et al. (1994) Cell 78, 325−334]. This structure represents a major step forward in efforts to design/discover potent selective inhibitors of the HPRT of T. cruzi.Keywords
This publication has 10 references indexed in Scilit:
- Hypoxanthine phosphoribosyltransferase from Trypanosoma cruzi as a target for structure-based inhibitor design: crystallization and inhibition studies with purine analogsAntimicrobial Agents and Chemotherapy, 1997
- The Conserved Serine-Tyrosine Dipeptide in Leishmania donovani Hypoxanthine-guanine Phosphoribosyltransferase Is Essential for Catalytic ActivityPublished by Elsevier ,1997
- The Crystal Structure of a Family 5 Endoglucanase Mutant in Complexed and Uncomplexed Forms Reveals an Induced Fit Activation MechanismJournal of Molecular Biology, 1996
- Structure of a novel extracellular Ca2+-binding module in BM-40Nature Structural & Molecular Biology, 1996
- Crystal Structure of Concanavalin B at 1.65 Å Resolution. An "Inactivated" Chitinase from Seeds ofCanavalia ensiformisJournal of Molecular Biology, 1995
- AMoRe: an automated package for molecular replacementActa Crystallographica Section A Foundations of Crystallography, 1994
- PROCHECK: a program to check the stereochemical quality of protein structuresJournal of Applied Crystallography, 1993
- Occurrence and role ofcis peptide bonds in protein structuresJournal of Molecular Biology, 1990
- Human hypoxanthine-guanine phosphoribosyltransferase. Steady state kinetics of the forward and reverse reactions.Journal of Biological Chemistry, 1978
- Primary 14C and alpha secondary 3H substrate kinetic isotope effects for some phosphoribosyltransferases.Journal of Biological Chemistry, 1978