1smc
Mycobacterium tuberculosis dUTPase complexed with dUTP in the absence of metal ion.
|
OverviewOverview
The structure of Mycobacterium tuberculosis dUTP nucleotidohydrolase, (dUTPase) has been determined at 1.3 Angstrom resolution in complex with, magnesium ion and the non-hydrolyzable substrate analog, alpha,beta-imido, dUTP. dUTPase is an enzyme essential for depleting potentially toxic, concentrations of dUTP in the cell. Given the importance of its biological, role, it has been proposed that inhibiting M.tuberculosis dUTPase might be, an effective means to treat tuberculosis infection in humans. The crystal, structure presented here offers some insight into the potential for, designing a specific inhibitor of the M.tuberculosis dUTPase enzyme. The, structure also offers new insights into the mechanism of dUTP hydrolysis, by providing an accurate representation of the enzyme-substrate complex in, which both the metal ion and dUTP analog are included. The structure, suggests that inclusion of a magnesium ion is important for stabilizing, the position of the alpha-phosphorus for an in-line nucleophilic attack., In the absence of magnesium, the alpha-phosphate of dUTP can have either, of the two positions which differ by 4.5 Angstrom. A transiently ordered, C-terminal loop further assists catalysis by shielding the general base, Asp83, from solvent thus elevating its pK(a) so that it might in turn, activate a tightly bound water molecule for nucleophilic attack. The metal, ion coordinates alpha, beta, and gamma phosphate groups with tridentate, geometry identical with that observed in the crystal structure of DNA, polymerase beta complexed with magnesium and dNTP analog, revealing some, common features in catalytic mechanism.
About this StructureAbout this Structure
1SMC is a Single protein structure of sequence from Mycobacterium tuberculosis with NO3, DUT and TRS as ligands. Active as dUTP diphosphatase, with EC number 3.6.1.23 Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of the Mycobacterium tuberculosis dUTPase: insights into the catalytic mechanism., Chan S, Segelke B, Lekin T, Krupka H, Cho US, Kim MY, So M, Kim CY, Naranjo CM, Rogers YC, Park MS, Waldo GS, Pashkov I, Cascio D, Perry JL, Sawaya MR, J Mol Biol. 2004 Aug 6;341(2):503-17. PMID:15276840
Page seeded by OCA on Wed Nov 21 02:28:59 2007