1. The Structure of Mammalian Serine Racemase.
- Author
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Smith, Myron A., Mack, Volker, Ebneth, Andreas, Moraes, Isabel, Felicetti, Brunella, Wood, Michael, Schonfeld, Dorian, Mather, Owen, Cesura, Andrea, and Barker, John
- Subjects
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SERINE , *METHYL aspartate , *GLUTAMIC acid , *BINDING sites , *ENZYMES , *CATALYSTS - 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 α,β-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-Å resolution, respectively, and in the presence and absence of the orthosteric inhibitor malonate. The structures revealed a fold typical of β-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. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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