The structure of mammalian serine racemase: evidence for conformational changes upon inhibitor binding.
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.
Smith
Myron A
MA
Department of Structural Biology and Biology, Evotec, 114 Milton Park, Abingdon, Oxon OX14 4SA, United Kingdom. myron.smith@evotec.com
Mack
Volker
V
Ebneth
Andreas
A
Moraes
Isabel
I
Felicetti
Brunella
B
Wood
Michael
M
Schonfeld
Dorian
D
Mather
Owen
O
Cesura
Andrea
A
Barker
John
J
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
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