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| Hauptseite > Publikationsdatenbank > Neutron and time-resolved X-ray crystallography reveal the substrate recognition and catalytic mechanism of human Nudix hydrolase MTH1 > print |
| Hauptseite > Publikationsdatenbank > Neutron and time-resolved X-ray crystallography reveal the substrate recognition and catalytic mechanism of human Nudix hydrolase MTH1 > print |
| 001 | 1047709 | ||
| 005 | 20251120202158.0 | ||
| 024 | 7 | _ | |a 10.1073/pnas.2510085122 |2 doi |
| 024 | 7 | _ | |a 0027-8424 |2 ISSN |
| 024 | 7 | _ | |a 1091-6490 |2 ISSN |
| 037 | _ | _ | |a FZJ-2025-04475 |
| 082 | _ | _ | |a 500 |
| 100 | 1 | _ | |a Hirata, Keisuke |0 P:(DE-HGF)0 |b 0 |
| 245 | _ | _ | |a Neutron and time-resolved X-ray crystallography reveal the substrate recognition and catalytic mechanism of human Nudix hydrolase MTH1 |
| 260 | _ | _ | |a Washington, DC |c 2025 |b National Acad. of Sciences |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 520 | _ | _ | |a Human MutT homolog 1 (MTH1/NUDT1), which belongs to the nucleoside diphosphate-linked moiety X (Nudix) hydrolase family, hydrolyzes oxidized nucleotides such as 8-oxo-dGTP and 2-oxo-dATP by its broad substrate specificity. MTH1 also attracts attention as a target molecule in cancer treatment and the broad substrate recognition of MTH1 is of biological and medical interests. Previous studies suggested that MTH1 exhibits the broad substrate recognition by changing the protonation state of Asp119 and Asp120 with much higher pKa. However, the recognition mechanism is not fully understood due to the difficulty of directly observing hydrogen atoms. In addition, recent time-resolved X-ray study proposed that the Nudix hydrolases catalyze the reactions through a new three-metal-ion mechanism rather than the two-metal-ion mechanism previously suggested. To understand the substrate recognition and catalytic mechanism of human MTH1, we have performed neutron and time-resolved X-ray crystallography. Neutron crystallography has visualized the protonation states of the active site residues, substrates, and water molecules which are crucial for the substrate-binding and catalysis, providing direct experimental evidence that the change in the protonation state of Asp119 and Asp120 is essential for the broad substrate recognition of MTH1. Time-resolved X-ray crystallography has visualized a whole reaction process catalyzed by MTH1 through three Mn2+ ions. Combination of neutron and time-resolved X-ray crystallography has proposed a three-metal-ion mechanism of MTH1 including nucleophilic substitution by a water molecule and its possible deprotonation pathway. The three-metal-ion mechanism would be a general feature in the catalytic reactions of the Nudix hydrolases. |
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| 700 | 1 | _ | |a Ostermann, Andreas |0 0000-0002-1477-5590 |b 2 |
| 700 | 1 | _ | |a Schrader, Tobias E. |0 P:(DE-Juel1)138266 |b 3 |
| 700 | 1 | _ | |a Hiromoto, Takeshi |0 0000-0002-8410-5111 |b 4 |
| 700 | 1 | _ | |a Goto, Masataka |0 P:(DE-HGF)0 |b 5 |
| 700 | 1 | _ | |a Arimori, Takao |0 0000-0002-6063-5572 |b 6 |
| 700 | 1 | _ | |a Hirano, Yu |0 0000-0002-3007-6052 |b 7 |
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| 700 | 1 | _ | |a Nakamura, Teruya |0 0000-0003-2013-3057 |b 10 |e Corresponding author |
| 773 | _ | _ | |a 10.1073/pnas.2510085122 |g Vol. 122, no. 29, p. e2510085122 |0 PERI:(DE-600)1461794-8 |n 29 |p e2510085122 |t Proceedings of the National Academy of Sciences of the United States of America |v 122 |y 2025 |x 0027-8424 |
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