1V3V

Crystal structure of leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase complexed with NADP and 15-oxo-PGE2

Summary for 1V3V

• Entry DOI: 10.2210/pdb1v3v/pdb
• Related: 1V3T 1V3U
• Descriptor: leukotriene b4 12-hydroxydehydrogenase/prostaglandin 15-keto reductase, CHLORIDE ION, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (5 entities in total)
• Functional Keywords: rossmann fold, riken structural genomics/proteomics initiative, rsgi, structural genomics, oxidoreductase
• Biological source: Cavia porcellus (domestic guinea pig)
• Cellular location: Cytoplasm (By similarity): Q9EQZ5
• Total number of polymer chains: 2
• Total formula weight: 74864.37

Authors

Hori, T.,Yokomizo, T.,Ago, H.,Sugahara, M.,Ueno, G.,Yamamoto, M.,Kumasaka, T.,Shimizu, T.,Miyano, M.,RIKEN Structural Genomics/Proteomics Initiative (RSGI) (deposition date: 2003-11-06, release date: 2004-07-13, Last modification date: 2023-12-27)

Primary citation

Hori, T.,Yokomizo, T.,Ago, H.,Sugahara, M.,Ueno, G.,Yamamoto, M.,Kumasaka, T.,Shimizu, T.,Miyano, M.
Structural basis of leukotriene B4 12-hydroxydehydrogenase/15-Oxo-prostaglandin 13-reductase catalytic mechanism and a possible Src homology 3 domain binding loop
J.Biol.Chem., 279:22615-22623, 2004

PubMed Abstract: The bifunctional leukotriene B(4) 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase (LTB(4) 12-HD/PGR) is an essential enzyme for eicosanoid inactivation. It is involved in the metabolism of the E and F series of 15-oxo-prostaglandins (15-oxo-PGs), leukotriene B(4) (LTB(4)), and 15-oxo-lipoxin A(4) (15-oxo-LXA(4)). Some nonsteroidal anti-inflammatory drugs (NSAIDs), which primarily act as cyclooxygenase inhibitors also inhibit LTB(4) 12-HD/PGR activity. Here we report the crystal structure of the LTB(4) 12-HD/PGR, the binary complex structure with NADP(+), and the ternary complex structure with NADP(+) and 15-oxo-PGE(2). In the ternary complex, both in the crystalline form and in solution, the enolate anion intermediate accumulates as a brown chromophore. PGE(2) contains two chains, but only the omega-chain of 15-oxo-PGE(2) was defined in the electron density map in the ternary complex structure. The omega-chain was identified at the hydrophobic pore on the dimer interface. The structure showed that the 15-oxo group forms hydrogen bonds with the 2'-hydroxyl group of nicotine amide ribose of NADP(+) and a bound water molecule to stabilize the enolate intermediate during the reductase reaction. The electron-deficient C13 atom of the conjugated enolate may be directly attacked by a hydride from the NADPH nicotine amide in a stereospecific manner. The moderate recognition of 15-oxo-PGE(2) is consistent with a broad substrate specificity of LTB(4) 12-HD/PGR. The structure also implies that a Src homology domain 3 may interact with the left-handed proline-rich helix at the dimer interface and regulate LTB(4) 12-HD/PGR activity by disruption of the substrate binding pore to accommodate the omega-chain.

PubMed: 15007077
DOI: 10.1074/jbc.M312655200

Experimental method

X-RAY DIFFRACTION (2 Å)