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@ARTICLE{Vandavasi:280722,
      author       = {Vandavasi, Venu Gopal and Weiss, Kevin L. and Cooper,
                      Jonathan B. and Erskine, Peter T. and Tomanicek, Stephen J.
                      and Ostermann, Andreas and Schrader, Tobias E. and Ginell,
                      Stephan L. and Coates, Leighton},
      title        = {{E}xploring the {M}echanism of β-{L}actam {R}ing
                      {P}rotonation in the {C}lass {A} β-lactamase {A}cylation
                      {M}echanism {U}sing {N}eutron and {X}-ray {C}rystallography},
      journal      = {Journal of medicinal chemistry},
      volume       = {59},
      issn         = {1520-4804},
      address      = {Washington, DC},
      publisher    = {ACS},
      reportid     = {FZJ-2016-00479},
      pages        = {acs.jmedchem.5b01215},
      year         = {2015},
      abstract     = {The catalytic mechanism of class A β-lactamases is often
                      debated due in part to the large number of amino acids that
                      interact with bound β-lactam substrates. The role and
                      function of the conserved residue Lys 73 in the catalytic
                      mechanism of class A type β-lactamase enzymes is still not
                      well understood after decades of scientific research. To
                      better elucidate the functions of this vital residue, we
                      used both neutron and high-resolution X-ray diffraction to
                      examine both the structures of the ligand free protein and
                      the acyl–enzyme complex of perdeuterated E166A Toho-1
                      β-lactamase with the antibiotic cefotaxime. The E166A
                      mutant lacks a critical glutamate residue that has a key
                      role in the deacylation step of the catalytic mechanism,
                      allowing the acyl–enzyme adduct to be captured for study.
                      In our ligand free structures, Lys 73 is present in a single
                      conformation, however in all of our acyl–enzyme
                      structures, Lys 73 is present in two different
                      conformations, in which one conformer is closer to Ser 70
                      while the other conformer is positioned closer to Ser 130,
                      which supports the existence of a possible pathway by which
                      proton transfer from Lys 73 to Ser 130 can occur. This and
                      further clarifications of the role of Lys 73 in the
                      acylation mechanism may facilitate the design of inhibitors
                      that capitalize on the enzyme’s native machinery.},
      cin          = {JCNS (München) ; Jülich Centre for Neutron Science JCNS
                      (München) ; JCNS-FRM-II / Neutronenstreuung ; JCNS-1},
      ddc          = {540},
      cid          = {I:(DE-Juel1)JCNS-FRM-II-20110218 /
                      I:(DE-Juel1)JCNS-1-20110106},
      pnm          = {6G15 - FRM II / MLZ (POF3-6G15) / 6G4 - Jülich Centre for
                      Neutron Research (JCNS) (POF3-623)},
      pid          = {G:(DE-HGF)POF3-6G15 / G:(DE-HGF)POF3-6G4},
      experiment   = {EXP:(DE-MLZ)BIODIFF-20140101},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000368564400033},
      pubmed       = {pmid:26630115},
      doi          = {10.1021/acs.jmedchem.5b01215},
      url          = {https://juser.fz-juelich.de/record/280722},
}