2DM6

Crystal structure of anti-configuration of indomethacin and leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase complex

Summary for 2DM6

• Entry DOI: 10.2210/pdb2dm6/pdb
• Related: 1V3T 1V3U 1V3V
• Descriptor: NADP-dependent leukotriene B4 12-hydroxydehydrogenase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, INDOMETHACIN, ... (5 entities in total)
• Functional Keywords: nad(p)-binding rossmann-fold domains, riken structural genomics/proteomics initiative, rsgi, structural genomics, oxidoreductase
• Biological source: Cavia porcellus (domestic guinea pig)
• Cellular location: Cytoplasm : Q9EQZ5
• Total number of polymer chains: 2
• Total formula weight: 74471.76

Authors

Hori, T.,Ishijima, J.,Yokomizo, T.,Ago, H.,Shimizu, T.,Miyano, M.,RIKEN Structural Genomics/Proteomics Initiative (RSGI) (deposition date: 2006-04-20, release date: 2006-11-28, Last modification date: 2024-10-23)

Primary citation

Hori, T.,Ishijima, J.,Yokomizo, T.,Ago, H.,Shimizu, T.,Miyano, M.
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
J.Biochem.(Tokyo), 140:457-466, 2006

PubMed 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.

PubMed: 16916844
DOI: 10.1093/jb/mvj176

Experimental method

X-RAY DIFFRACTION (2 Å)