No abstract

The crystal structure of hPEBP suggests that the ligand-binding site could accommodate the phosphate head groups of membrane lipids, therefore allowing the protein to adhere to the inner leaf of bilipid membranes where it would be ideally positioned to relay signals from the membrane to the cytoplasm. The structure also suggests that ligand binding may lead to coordinated release of the N-terminal region of the protein to form the hippocampal neurostimulatory peptide, which is known to be active in the development of the hippocampus. These studies are consistent with a primary biological role for hPEBP as a transducer of signals from the interior membrane surface.

An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.

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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-phosphatedependent enzyme is involved both in the reversible conversion of L-to D-serine and serine catabolism by ␣,␤-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 ␤-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.N-Methyl-D-aspartate receptor-type glutamate receptors (NMDARs) 2 are a key component in glutamatergic transmission implicated in the development, function, and plasticity of the nervous system. In addition to the neurotransmitter glutamate, the activation of NMDARs requires the binding of either of the two endogenous co-agonists, glycine or D-serine, to the NMDAR "glycine modulatory site" (1, 2). Although both amino acids have similar potency as co-agonists, they display regional differences in modulating NMDAR function (3, 4). According to its distribution within the CNS, D-serine exerts its function predominantly in corticolimbic brain structures (5). This pivotal role of D-serine is supported by several experimental findings, including depletion studies in neuronal tissue preparations, indicating a strong reduction in NMDAR-mediated transmission and impaired synaptic plasticity in the absence of D-serine (6, 7).D-serine is produced by enzymatic conversion of L-to D-serine mediated by the pyridoxal 5Ј-phosphate (PLP)-containing enzyme serine racemase (SR). Mammalian SR was first purified from rat brain and functionally characterized in 1999 by Wolosker and colleagues (8). The enzyme is expressed in glial cells and neurons and constitutes the sole endogenous source for D-serine in mammals (9). Both human and rodent SR have been purified and extensively studied to generate comprehensive knowledge of the enzymatic characteristics and allosteric modulation by a number of agents such as ATP and Mg 2ϩ ions. In addition to serine isomerization, the enzyme catalyzes the ␣,␤-elimination of water from L-and D-serine to produce pyruvate and ammonia, thus, offering the possibility for SR not only to elevate but also to reduce the level of D-serine (5), a role that previously has mainly been attributed to D-amino acid oxidase (10).Recent data from SR-deficient mice strongly implicate this enzyme in the process of NMDAR-dependent plasticity and neurotoxicity. Knock-out mice were ...