2pno
From Proteopedia
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==Overview== | ==Overview== | ||
| - | The cysteinyl leukotrienes, namely leukotriene (LT)C4 and its metabolites | + | The cysteinyl leukotrienes, namely leukotriene (LT)C4 and its metabolites LTD4 and LTE4, the components of slow-reacting substance of anaphylaxis, are lipid mediators of smooth muscle constriction and inflammation, particularly implicated in bronchial asthma. LTC4 synthase (LTC4S), the pivotal enzyme for the biosynthesis of LTC4 (ref. 10), is an 18-kDa integral nuclear membrane protein that belongs to a superfamily of membrane-associated proteins in eicosanoid and glutathione metabolism that includes 5-lipoxygenase-activating protein, microsomal glutathione S-transferases (MGSTs), and microsomal prostaglandin E synthase 1 (ref. 13). LTC4S conjugates glutathione to LTA4, the endogenous substrate derived from arachidonic acid through the 5-lipoxygenase pathway. In contrast with MGST2 and MGST3 (refs 15, 16), LTC4S does not conjugate glutathione to xenobiotics. Here we show the atomic structure of human LTC4S in a complex with glutathione at 3.3 A resolution by X-ray crystallography and provide insights into the high substrate specificity for glutathione and LTA4 that distinguishes LTC4S from other MGSTs. The LTC4S monomer has four transmembrane alpha-helices and forms a threefold symmetric trimer as a unit with functional domains across each interface. Glutathione resides in a U-shaped conformation within an interface between adjacent monomers, and this binding is stabilized by a loop structure at the top of the interface. LTA4 would fit into the interface so that Arg 104 of one monomer activates glutathione to provide the thiolate anion that attacks C6 of LTA4 to form a thioether bond, and Arg 31 in the neighbouring monomer donates a proton to form a hydroxyl group at C5, resulting in 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid (LTC4). These findings provide a structural basis for the development of LTC4S inhibitors for a proinflammatory pathway mediated by three cysteinyl leukotriene ligands whose stability and potency are different and by multiple cysteinyl leukotriene receptors whose functions may be non-redundant. |
| + | |||
| + | ==Disease== | ||
| + | Known disease associated with this structure: Leukotriene C4 synthase deficiency OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=246530 246530]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Ago, H.]] | [[Category: Ago, H.]] | ||
| - | [[Category: Austen, K | + | [[Category: Austen, K F.]] |
[[Category: Irikura, D.]] | [[Category: Irikura, D.]] | ||
[[Category: Kanaoka, Y.]] | [[Category: Kanaoka, Y.]] | ||
| - | [[Category: Lam, B | + | [[Category: Lam, B K.]] |
[[Category: Miyano, M.]] | [[Category: Miyano, M.]] | ||
[[Category: Shimamura, T.]] | [[Category: Shimamura, T.]] | ||
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[[Category: mgst]] | [[Category: mgst]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:31:24 2008'' |
Revision as of 16:31, 21 February 2008
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Crystal structure of human leukotriene C4 synthase
Contents |
Overview
The cysteinyl leukotrienes, namely leukotriene (LT)C4 and its metabolites LTD4 and LTE4, the components of slow-reacting substance of anaphylaxis, are lipid mediators of smooth muscle constriction and inflammation, particularly implicated in bronchial asthma. LTC4 synthase (LTC4S), the pivotal enzyme for the biosynthesis of LTC4 (ref. 10), is an 18-kDa integral nuclear membrane protein that belongs to a superfamily of membrane-associated proteins in eicosanoid and glutathione metabolism that includes 5-lipoxygenase-activating protein, microsomal glutathione S-transferases (MGSTs), and microsomal prostaglandin E synthase 1 (ref. 13). LTC4S conjugates glutathione to LTA4, the endogenous substrate derived from arachidonic acid through the 5-lipoxygenase pathway. In contrast with MGST2 and MGST3 (refs 15, 16), LTC4S does not conjugate glutathione to xenobiotics. Here we show the atomic structure of human LTC4S in a complex with glutathione at 3.3 A resolution by X-ray crystallography and provide insights into the high substrate specificity for glutathione and LTA4 that distinguishes LTC4S from other MGSTs. The LTC4S monomer has four transmembrane alpha-helices and forms a threefold symmetric trimer as a unit with functional domains across each interface. Glutathione resides in a U-shaped conformation within an interface between adjacent monomers, and this binding is stabilized by a loop structure at the top of the interface. LTA4 would fit into the interface so that Arg 104 of one monomer activates glutathione to provide the thiolate anion that attacks C6 of LTA4 to form a thioether bond, and Arg 31 in the neighbouring monomer donates a proton to form a hydroxyl group at C5, resulting in 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid (LTC4). These findings provide a structural basis for the development of LTC4S inhibitors for a proinflammatory pathway mediated by three cysteinyl leukotriene ligands whose stability and potency are different and by multiple cysteinyl leukotriene receptors whose functions may be non-redundant.
Disease
Known disease associated with this structure: Leukotriene C4 synthase deficiency OMIM:[246530]
About this Structure
2PNO is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Leukotriene-C(4) synthase, with EC number 4.4.1.20 Full crystallographic information is available from OCA.
Reference
Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis., Ago H, Kanaoka Y, Irikura D, Lam BK, Shimamura T, Austen KF, Miyano M, Nature. 2007 Aug 2;448(7153):609-12. Epub 2007 Jul 15. PMID:17632548
Page seeded by OCA on Thu Feb 21 18:31:24 2008
Categories: Homo sapiens | Leukotriene-C(4) synthase | Single protein | Ago, H. | Austen, K F. | Irikura, D. | Kanaoka, Y. | Lam, B K. | Miyano, M. | Shimamura, T. | GTT | LMT | Helix bundle | Homo trimer | Lyase | Mapeg | Membrane protein | Mgst
