3AC9

Crystal structure of human NUDT5 complexed with 8-oxo-dGDP and manganese

Summary for 3AC9

• Entry DOI: 10.2210/pdb3ac9/pdb
• Related: 3ACA 3L85
• Descriptor: ADP-sugar pyrophosphatase, 2'-deoxy-8-oxoguanosine 5'-(trihydrogen diphosphate), MANGANESE (II) ION, ... (4 entities in total)
• Functional Keywords: nudix motif, magnesium, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 44283.46

Authors

Arimori, T.,Yamagata, Y. (deposition date: 2009-12-30, release date: 2011-01-12, Last modification date: 2023-11-01)

Primary citation

Arimori, T.,Tamaoki, H.,Nakamura, T.,Kamiya, H.,Ikemizu, S.,Takagi, Y.,Ishibashi, T.,Harashima, H.,Sekiguchi, M.,Yamagata, Y.
Diverse substrate recognition and hydrolysis mechanisms of human NUDT5
Nucleic Acids Res., 39:8972-8983, 2011

PubMed Abstract: Human NUDT5 (hNUDT5) hydrolyzes various modified nucleoside diphosphates including 8-oxo-dGDP, 8-oxo-dADP and ADP-ribose (ADPR). However, the structural basis of the broad substrate specificity remains unknown. Here, we report the crystal structures of hNUDT5 complexed with 8-oxo-dGDP and 8-oxo-dADP. These structures reveal an unusually different substrate-binding mode. In particular, the positions of two phosphates (α and β phosphates) of substrate in the 8-oxo-dGDP and 8-oxo-dADP complexes are completely inverted compared with those in the previously reported hNUDT5-ADPR complex structure. This result suggests that the nucleophilic substitution sites of the substrates involved in hydrolysis reactions differ despite the similarities in the chemical structures of the substrates and products. To clarify this hypothesis, we employed the isotope-labeling method and revealed that 8-oxo-dGDP is attacked by nucleophilic water at Pβ, whereas ADPR is attacked at Pα. This observation reveals that the broad substrate specificity of hNUDT5 is achieved by a diversity of not only substrate recognition, but also hydrolysis mechanisms and leads to a novel aspect that enzymes do not always catalyze the reaction of substrates with similar chemical structures by using the chemically equivalent reaction site.

PubMed: 21768126
DOI: 10.1093/nar/gkr575

Experimental method

X-RAY DIFFRACTION (2.1 Å)