TY - JOUR
T1 - Structure and mechanism of MT-ADPRase, a Nudix hydrolase from Mycobacterium tuberculosis
AU - Kang, Lin Woo
AU - Gabelli, Sandra B.
AU - Cunningham, Jennifer E.
AU - O'Handley, Suzanne F.
AU - Amzel, L. Mario
N1 - Funding Information:
This work was supported by NIH grants AI49485 and GM066895, grant J-497 from the Jeffress Trust Foundation, and a Cottrell College Science Award (CC5180) from Research Corporation. We thank Dr. Mario A. Bianchet for help throughout this project, Dr. Y. Zhang for his guidance with M. tuberculosis, and Dr. M. Bessman for discussions on Nudix enzymes.
PY - 2003/8/1
Y1 - 2003/8/1
N2 - Nudix hydrolases are a family of proteins that contain the characteristic sequence GX5EX7REUXEEXG(I/L/V), the Nudix box. They catalyze the hydrolysis of a variety of nucleoside diphosphate derivatives such as ADP-ribose, ApnA (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 Gd3+, and in complex with a nonhydrolyzable ADPR analog and the activating metal ion Mn2+. These structures, refined with data extending to resolutions between 2.0 and 2.3 Å, 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.
AB - Nudix hydrolases are a family of proteins that contain the characteristic sequence GX5EX7REUXEEXG(I/L/V), the Nudix box. They catalyze the hydrolysis of a variety of nucleoside diphosphate derivatives such as ADP-ribose, ApnA (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 Gd3+, and in complex with a nonhydrolyzable ADPR analog and the activating metal ion Mn2+. These structures, refined with data extending to resolutions between 2.0 and 2.3 Å, 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.
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U2 - 10.1016/S0969-2126(03)00154-0
DO - 10.1016/S0969-2126(03)00154-0
M3 - Article
C2 - 12906832
AN - SCOPUS:0043133626
SN - 0969-2126
VL - 11
SP - 1015
EP - 1023
JO - Structure with Folding & design
JF - Structure with Folding & design
IS - 8
ER -