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Journal of Biochemistry Advance Access published online on August 17, 2006
Journal of Biochemistry, doi:10.1093/jb/mvj176
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© 2006 The Japanese Biochemical Society.
Received June 23, 2006
Accepted August 10, 2006

Regular Paper

Crystal Structure of Anti-Configuration of Indomethacin and Leukotriene B4 12-Hydroxydehydrogenase/15-Oxo-Prostaglandin 13-Reductase Complex Reveals the Structural Basis of Broad Spectrum Indomethacin Efficacy

Tetsuya Hori 1, Jun Ishijima 1, Takehiko Yokomizo 2, Hideo Ago 1, Takao Shimizu 3, and Masashi Miyano 1 *

1 Structural Biophysics Laboratory, RIKEN SPring-8 Center, Harima Institute, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo 679-5148, Japan
2 Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo, Japan; Core Research for Evolutional Science and Technology of Japan Science and Technology Agency, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan
3 Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, Tokyo, Japan

* To whom correspondence should be addressed.
Masashi Miyano, E-mail: miyano{at}spring8.or.jp


  Abstract

The crystal structure of the ternary complex of leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin (15-oxo-PG) 13-reductase (LTB4 12HD/PGR), an essential enzyme for eicosanoid inactivation pathways, with indomethacin and NADP+ has been solved. An indomethacin molecule bound in the anti-configuration at one of the two active site clefts of the homo-dimer interface in the LTB4 12HD/PGR and was confirmed by a binding calorimetry. The chlorobenzene ring is buried in the hydrophobic pore used as a binding site by the {omega}-chain of 15-oxo-PGE2. The carboxyl group interacts with the guanidino group of Arg56 and the phenolic hydroxyl group of Tyr262. Indomethacin shows a broad spectrum of efficacy against lipid-mediator related proteins including cyclooxygenase-2, phospholipase A2, PGF synthase and PGE synthase-2 but in the syn-configuration as well as LTB4 12HD/PGR in the anti-configuration. Indomethacin does not necessarily mimic the binding mode of the lipid-mediator substrates in the active sites of these complex structures. Thus, the broad spectrum of indomethacin efficacy can be attributed to its ability to adopt a range of different stable conformations. This allows the indomethacin to adapt to the distinct binding site features of each protein whilst maintaining favorable interactions between the carboxyl group and a counter charged functional group.

Keywords: Crystal structure; Indomethacin; Inhibition mechanism; Leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase; Isothermal titration calorimetry.
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