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    J Biol Chem. 2010 Apr 23;285(17):12873-81. Epub 2010 Jan 27.

    The structure of mammalian serine racemase: evidence for conformational changes upon inhibitor binding.

    Smith MA, Mack V, Ebneth A, Moraes I, Felicetti B, Wood M, Schonfeld D, Mather O, Cesura A, Barker J.

    Source

    Department of Structural Biology and Biology, Evotec, 114 Milton Park, Abingdon, Oxon OX14 4SA, United Kingdom. myron.smith@evotec.com

    Abstract

    Serine racemase is responsible for the synthesis of D-serine, an endogenous co-agonist for N-methyl-D-aspartate receptor-type glutamate receptors (NMDARs). This pyridoxal 5'-phosphate-dependent enzyme is involved both in the reversible conversion of L- to D-serine and serine catabolism by alpha,beta-elimination of water, thereby regulating D-serine levels. Because D-serine affects NMDAR signaling throughout the brain, serine racemase is a promising target for the treatment of disorders related to NMDAR dysfunction. To provide a molecular basis for rational drug design the x-ray crystal structures of human and rat serine racemase were determined at 1.5- and 2.1-A resolution, respectively, and in the presence and absence of the orthosteric inhibitor malonate. The structures revealed a fold typical of beta-family pyridoxal 5'-phosphate enzymes, with both a large domain and a flexible small domain associated into a symmetric dimer, and indicated a ligand-induced rearrangement of the small domain that organizes the active site for specific turnover of the substrate.

    PMID:
    20106978
    [PubMed - indexed for MEDLINE]
    PMCID:
    PMC2857111
    Free PMC Article

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