The structure of mammalian serine racemase: evidence for conformational changes upon inhibitor binding.
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Smith MA, Mack V, Ebneth A, Moraes I, Felicetti B, Wood M, Schonfeld D, Mather O, Cesura A, Barker J
The structure of mammalian serine racemase: evidence for conformational changes upon inhibitor binding.
J Biol Chem. 2010 Apr 23;285(17):12873-81. doi: 10.1074/jbc.M109.050062. Epub 2010 Jan 27.
- PubMed ID
- 20106978 [ View in PubMed]
- 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.