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@ARTICLE{Hirata:1047709,
      author       = {Hirata, Keisuke and Fujimiya, Kana and Ostermann, Andreas
                      and Schrader, Tobias E. and Hiromoto, Takeshi and Goto,
                      Masataka and Arimori, Takao and Hirano, Yu and Kusaka,
                      Katsuhiro and Tamada, Taro and Nakamura, Teruya},
      title        = {{N}eutron and time-resolved {X}-ray crystallography reveal
                      the substrate recognition and catalytic mechanism of human
                      {N}udix hydrolase {MTH}1},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {122},
      number       = {29},
      issn         = {0027-8424},
      address      = {Washington, DC},
      publisher    = {National Acad. of Sciences},
      reportid     = {FZJ-2025-04475},
      pages        = {e2510085122},
      year         = {2025},
      abstract     = {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.},
      cin          = {JCNS-FRM-II / MLZ / JCNS-4},
      ddc          = {500},
      cid          = {I:(DE-Juel1)JCNS-FRM-II-20110218 / I:(DE-588b)4597118-3 /
                      I:(DE-Juel1)JCNS-4-20201012},
      pnm          = {6G4 - Jülich Centre for Neutron Research (JCNS) (FZJ)
                      (POF4-6G4) / 632 - Materials – Quantum, Complex and
                      Functional Materials (POF4-632)},
      pid          = {G:(DE-HGF)POF4-6G4 / G:(DE-HGF)POF4-632},
      experiment   = {EXP:(DE-MLZ)BIODIFF-20140101},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1073/pnas.2510085122},
      url          = {https://juser.fz-juelich.de/record/1047709},
}