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spinqualitylabelsall models 1v3v, resolution 2.0Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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

Overview

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.

About this Structure

1V3V is a Single protein structure of sequence from Cavia porcellus with CL, NAP and 5OP as ligands. Active as 15-oxoprostaglandin 13-oxidase, with EC number 1.3.1.48 Full crystallographic information is available from OCA.

Reference

Structural basis of leukotriene B4 12-hydroxydehydrogenase/15-Oxo-prostaglandin 13-reductase catalytic mechanism and a possible Src homology 3 domain binding loop., Hori T, Yokomizo T, Ago H, Sugahara M, Ueno G, Yamamoto M, Kumasaka T, Shimizu T, Miyano M, J Biol Chem. 2004 May 21;279(21):22615-23. Epub 2004 Mar 8. PMID:15007077

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