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J. Biol. Chem., Vol. 279, Issue 21, 22615-22623, May 21, 2004

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Structural Basis of Leukotriene B₄ 12-Hydroxydehydrogenase/15-Oxo-prostaglandin 13-Reductase Catalytic Mechanism and a Possible Src Homology 3 Domain Binding Loop^*

From the ^aStructural Biophysics Laboratory, ^eHighthroughput Factory, ^fCoherent X-ray Optics Laboratory, RIKEN Harima Institute at SPring-8, 1-1-1 Kouto, Mikazuki, Sayo-gun, Hyogo 679-5148, the ^bDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, University of Tokyo, ^cCore Research for Evolutional Science and Technology, and ^dPrecursory Research for Embryonic Science and Technology of Japan Science and Technology Agency, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan

The bifunctional leukotriene B₄ 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase (LTB₄ 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 B₄ (LTB₄), and 15-oxo-lipoxin A₄ (15-oxo-LXA₄). Some nonsteroidal anti-inflammatory drugs (NSAIDs), which primarily act as cyclooxygenase inhibitors also inhibit LTB₄ 12-HD/PGR activity. Here we report the crystal structure of the LTB₄ 12-HD/PGR, the binary complex structure with NADP⁺, and the ternary complex structure with NADP⁺ and 15-oxo-PGE₂. In the ternary complex, both in the crystalline form and in solution, the enolate anion intermediate accumulates as a brown chromophore. PGE₂ contains two chains, but only the -chain of 15-oxo-PGE₂ was defined in the electron density map in the ternary complex structure. The -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-PGE₂ is consistent with a broad substrate specificity of LTB₄ 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 LTB₄ 12-HD/PGR activity by disruption of the substrate binding pore to accommodate the -chain.

Received for publication, November 19, 2003 , and in revised form, March 1, 2004.

The atomic coordinates and structure factors (code 1V3T, 1V3U, and 1V3V) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by a grant from the Special Postdoctoral Researchers Program in RIKEN (to T. H.) and by the National Project on Protein Structural and Functional Analysis funded by the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^g On leave from Rigaku Co., Tokyo 196-8666, Japan.

^h Present address: Tokyo Institute of Technology, Yokohama 226-8501, Japan.

ⁱ To whom correspondence should be addressed: Structural Biophysics Laboratory, RIKEN Harima Institute, 1-1-1 Kouto, Mikazuki, Sayogun, Hyogo 679-5148, Japan. Tel.: 81-791-58-2815; Fax: 81-791-58-2816; E-mail: miyano{at}spring8.or.jp.

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