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@ARTICLE{Oppici:166796,
      author       = {Oppici, Elisa and Fodor, Krisztian and Paiardini,
                      Alessandro and Williams, Chris and Voltattorni, Carla Borri
                      and Wilmanns, Matthias and Cellini, Barbara},
      title        = {{C}rystal structure of the {S}187{F} variant of human liver
                      alanine: {A}minotransferase associated with primary
                      hyperoxaluria type {I} and its functional implications},
      journal      = {Proteins},
      volume       = {81},
      number       = {8},
      issn         = {0887-3585},
      address      = {New York, NY},
      publisher    = {Wiley-Liss},
      reportid     = {DESY-2014-01630},
      pages        = {1457 - 1465},
      year         = {2013},
      note         = {(c) WILEY PERIODICALS, INC},
      abstract     = {The substitution of Ser187, a residue located far from the
                      active site of human liver peroxisomal alanine:glyoxylate
                      aminotransferase (AGT), by Phe gives rise to a variant
                      associated with primary hyperoxaluria type I. Unexpectedly,
                      previous studies revealed that the recombinant form of S187F
                      exhibits a remarkable loss of catalytic activity, an
                      increased pyridoxal 5'-phosphate (PLP) binding affinity and
                      a different coenzyme binding mode compared with normal AGT.
                      To shed light on the structural elements responsible for
                      these defects, we solved the crystal structure of the
                      variant to a resolution of 2.9 Å. Although the overall
                      conformation of the variant is similar to that of normal
                      AGT, we noticed: (i) a displacement of the PLP-binding
                      Lys209 and Val185, located on the re and si side of PLP,
                      respectively, and (ii) slight conformational changes of
                      other active site residues, in particular Trp108, the base
                      stacking residue with the pyridine cofactor moiety. This
                      active site perturbation results in a mispositioning of the
                      AGT-pyridoxamine 5'-phosphate (PMP) complex and of the
                      external aldimine, as predicted by molecular modeling
                      studies. Taken together, both predicted and observed
                      movements caused by the S187F mutation are consistent with
                      the following functional properties of the variant: (i) a
                      300- to 500-fold decrease in both the rate constant of
                      L-alanine half-transamination and the kcat of the overall
                      transamination, (ii) a different PMP binding mode and
                      affinity, and (iii) a different microenvironment of the
                      external aldimine. Proposals for the treatment of patients
                      bearing S187F mutation are discussed on the basis of these
                      results.},
      cin          = {EMBL},
      ddc          = {540},
      cid          = {I:(DE-H253)EMBL-20120731},
      pnm          = {DORIS Beamline K1.3 (POF2-54G13)},
      pid          = {G:(DE-H253)POF2-K1.3-20130405},
      experiment   = {EXP:(DE-H253)D-K1.3-20150101},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000329220400015},
      pubmed       = {pmid:23589421},
      doi          = {10.1002/prot.24300},
      url          = {https://bib-pubdb1.desy.de/record/166796},
}