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

Authors: Hori, Tetsuya; Ishijima, Jun; Yokomizo, Takehiko; Ago, Hideo; Shimizu, Takao; Miyano, Masashi

Source: The Journal of Biochemistry, Volume 140, Number 3, September 2006 , pp. 457-466(10)

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Abstract:

The crystal structure of the ternary complex of leukotriene B<inf>4</inf> 12-hydroxydehydrogenase/15-oxo-prostaglandin (15-oxo-PG) 13-reductase (LTB<inf>4</inf> 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 LTB<inf>4</inf> 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 ω-chain of 15-oxo-PGE<inf>2</inf>. 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 A<inf>2</inf>, PGF synthase and PGE synthase-2 but in the syn-configuration as well as LTB<inf>4</inf> 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.

Document Type: Research article

DOI: http://dx.doi.org/10.1093/jb/mvj176

Publication date: 2006-09-01