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Analyses of 3-D Structure of PGDS

We are resolving the 3-D structures of these two types of PGD synthase, one is lipocalin-type PGD synthase (L-PGDS) and the other is hematopoietic PGD synthase (H-PGDS), by X-ray crystallographic analysis and NMR spectroscopy so that we may elucidate their catalytic mechanisms in order to design and develop new drugs that are selective or nonselective for these enzymes.

We succeeded in the crystallization of lipocalin-type PGD synthase (L-PGDS), and also hematopoietic PGD synthase (H-PGDS).

L-PGDS is localized in the central nervous system, male genital organs, cardiovascular system and adipocytes. On the other hand, H-PGDS is localized in mast cells, megakaryocytes and necrotic muscle in the case of muscular dystrophy.

1) Protein Structure Analyses

L-PGDS shows a typical lipocalin fold, and consists of a single domain made up of an eight-stranded antiparallel beta-sheet, three α-helical regions, and a C-terminal strand.

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H-PGDS is a homodimer containing a Ca²⁺ or Mg²⁺ ion at the center of the dimer interface.

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We found a novel orally active H-PGDS inhibitor (HQL-79) and determined the 3-D structure of the HQL-79/ H-PGDS complex by X-ray crystallographic analysis (Aritake, K. et al., J.Biol. Chem, 2006). We also found a novel orally active L-PGDS inhibitor (AT-56) and determined the solution structure of AT-56/L-PGDS complex by NMR analysis (Irikura, D. et al., J.Biol. Chem, 2009).

These data provide us with information that will enable us to construct selective and potent H-PGDS inhibitors.

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1) Space Experiment

We are conducting joint research with the Japan Aerospace Exploration Agency (JAXA), using a Russian command-service module in space to study protein crystal growth. On August 2007, loaded with our enzyme, the unmanned space supply vessel “Progress” lifted off from launch pad in Baikonur, Kazakhstan to, the international Space Station (ISS). After the two-month experiment in “KIBOU, the Japanese Experiment Module” at orbit, the “Soyuz” spacecraft-instrumented protein crystal growth cryostat returned safely with the enzyme. We obtained high-quality crystals, and by using an intense X-ray at the SPring-8 synchrotron facility, we have determined the three-dimensional structures of H-PGD crystals produced under microgravity. Our goal is to design drugs logically based on their 3D structure.

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