title: The structure of mammalian serine racemase: evidence for conformational changes upon inhibitor binding.
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.
authors.affiliation: Department of Structural Biology and Biology, Evotec, 114 Milton Park, Abingdon, Oxon OX14 4SA, United Kingdom. myron.smith@evotec.com
authors.forename: Myron A
authors.initials: MA
authors.lastname: Smith
authors.forename: Volker
authors.initials: V
authors.lastname: Mack
authors.forename: Andreas
authors.initials: A
authors.lastname: Ebneth
authors.forename: Isabel
authors.initials: I
authors.lastname: Moraes
authors.forename: Brunella
authors.initials: B
authors.lastname: Felicetti
authors.forename: Michael
authors.initials: M
authors.lastname: Wood
authors.forename: Dorian
authors.initials: D
authors.lastname: Schonfeld
authors.forename: Owen
authors.initials: O
authors.lastname: Mather
authors.forename: Andrea
authors.initials: A
authors.lastname: Cesura
authors.forename: John
authors.initials: J
authors.lastname: Barker
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008314:Malonates / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011732:Pyridoxal Phosphate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019998:Racemases and Epimerases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000096:biosynthesis / Q000235:genetics; D000099300:Serine Racemase
chemical_list: D004791:Enzyme Inhibitors; D008314:Malonates; D011732:Pyridoxal Phosphate; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000099300:Serine Racemase; C030290:malonic acid