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1v3v
From Proteopedia
(New page: 200px<br /><applet load="1v3v" size="450" color="white" frame="true" align="right" spinBox="true" caption="1v3v, resolution 2.0Å" /> '''Crystal structure of ...) |
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| - | [[Image:1v3v.gif|left|200px]]<br /><applet load="1v3v" size=" | + | [[Image:1v3v.gif|left|200px]]<br /><applet load="1v3v" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1v3v, resolution 2.0Å" /> | caption="1v3v, resolution 2.0Å" /> | ||
'''Crystal structure of leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase complexed with NADP and 15-oxo-PGE2'''<br /> | '''Crystal structure of leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase complexed with NADP and 15-oxo-PGE2'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The bifunctional leukotriene B(4) | + | 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== | ==About this Structure== | ||
| - | 1V3V is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Cavia_porcellus Cavia porcellus] with CL, NAP and 5OP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/15-oxoprostaglandin_13-oxidase 15-oxoprostaglandin 13-oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.48 1.3.1.48] Full crystallographic information is available from [http:// | + | 1V3V is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Cavia_porcellus Cavia porcellus] with <scene name='pdbligand=CL:'>CL</scene>, <scene name='pdbligand=NAP:'>NAP</scene> and <scene name='pdbligand=5OP:'>5OP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/15-oxoprostaglandin_13-oxidase 15-oxoprostaglandin 13-oxidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.48 1.3.1.48] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1V3V OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Kumasaka, T.]] | [[Category: Kumasaka, T.]] | ||
[[Category: Miyano, M.]] | [[Category: Miyano, M.]] | ||
| - | [[Category: RSGI, RIKEN | + | [[Category: RSGI, RIKEN Structural Genomics/Proteomics Initiative.]] |
[[Category: Shimizu, T.]] | [[Category: Shimizu, T.]] | ||
[[Category: Sugahara, M.]] | [[Category: Sugahara, M.]] | ||
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[[Category: structural genomics]] | [[Category: structural genomics]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:31:13 2008'' |
Revision as of 13:31, 21 February 2008
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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 , and 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
Page seeded by OCA on Thu Feb 21 15:31:13 2008
Categories: 15-oxoprostaglandin 13-oxidase | Cavia porcellus | Single protein | Ago, H. | Hori, T. | Kumasaka, T. | Miyano, M. | RSGI, RIKEN Structural Genomics/Proteomics Initiative. | Shimizu, T. | Sugahara, M. | Ueno, G. | Yamamoto, M. | Yokomizo, T. | 5OP | CL | NAP | Riken structural genomics/proteomics initiative | Rossmann fold | Rsgi | Structural genomics
