Structure and mechanism of MT-ADPRase, a nudix hydrolase from Mycobacterium tuberculosis.

Abstract

Nudix hydrolases are a family of proteins that contain the characteristic sequence GX(5)EX(7)REUXEEXG(I/L/V), the Nudix box. They catalyze the hydrolysis of a variety of nucleoside diphosphate derivatives such as ADP-ribose, Ap(n)A (3 </= n </= 6), NADH, and dATP. A number of Nudix hydrolases from several species, ranging from bacteria to humans, have been characterized, including, in some cases, the determination of their three-dimensional structures. The product of the Rv1700 gene of M. tuberculosis is a Nudix hydrolase specific for ADP-ribose (ADPR). We have determined the crystal structures of MT-ADPRase alone, and in complex with substrate, with substrate and the nonactivating metal ion Gd(3+), and in complex with a nonhydrolyzable ADPR analog and the activating metal ion Mn(2+). These structures, refined with data extending to resolutions between 2.0 and 2.3 A, showed that there are sequence differences in binding site residues between MT-ADPRase and a human homolog that may be exploited for antituberculosis drug development.

• Authors: Lin-Woo Kang, Sandra B Gabelli, Jennifer E Cunningham, Suzanne F O'Handley, L Mario Amzel
• Journal: Structure (London, England : 1993) (Structure) Vol. 11 Issue 8 Pg. 1015-23 (Aug 2003) ISSN: 0969-2126 [Print] United States
• PMID: 12906832 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Ligands
• Water
• Adenosine Diphosphate Ribose
• Manganese
• Gadolinium
• Hydrolases
• Pyrophosphatases

Topics

• Adenosine Diphosphate Ribose (metabolism)
• Amino Acid Sequence
• Binding Sites
• Catalysis
• Crystallography, X-Ray
• Dimerization
• Enzyme Activation
• Escherichia coli (enzymology)
• Gadolinium (metabolism)
• Helix-Loop-Helix Motifs
• Humans
• Hydrogen Bonding
• Hydrolases (chemistry)
• Ligands
• Manganese (metabolism)
• Models, Molecular
• Molecular Sequence Data
• Molecular Structure
• Mycobacterium tuberculosis (enzymology, genetics)
• Protein Conformation
• Protein Structure, Tertiary
• Pyrophosphatases (chemistry)
• Sequence Homology, Amino Acid
• Species Specificity
• Substrate Specificity
• Water (chemistry)