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| [[Image:2uuh.gif|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_2uuh| PDB=2uuh | SCENE= }} | | {{STRUCTURE_2uuh| PDB=2uuh | SCENE= }} |
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| '''CRYSTAL STRUCTURE OF HUMAN LEUKOTRIENE C4 SYNTHASE IN COMPLEX WITH SUBSTRATE GLUTATHIONE'''
| | ===CRYSTAL STRUCTURE OF HUMAN LEUKOTRIENE C4 SYNTHASE IN COMPLEX WITH SUBSTRATE GLUTATHIONE=== |
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| ==Overview==
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| Cysteinyl leukotrienes are key mediators in inflammation and have an important role in acute and chronic inflammatory diseases of the cardiovascular and respiratory systems, in particular bronchial asthma. In the biosynthesis of cysteinyl leukotrienes, conversion of arachidonic acid forms the unstable epoxide leukotriene A4 (LTA4). This intermediate is conjugated with glutathione (GSH) to produce leukotriene C4 (LTC4) in a reaction catalysed by LTC4 synthase: this reaction is the key step in cysteinyl leukotriene formation. Here we present the crystal structure of the human LTC4 synthase in its apo and GSH-complexed forms to 2.00 and 2.15 A resolution, respectively. The structure reveals a homotrimer, where each monomer is composed of four transmembrane segments. The structure of the enzyme in complex with substrate reveals that the active site enforces a horseshoe-shaped conformation on GSH, and effectively positions the thiol group for activation by a nearby arginine at the membrane-enzyme interface. In addition, the structure provides a model for how the omega-end of the lipophilic co-substrate is pinned at one end of a hydrophobic cleft, providing a molecular 'ruler' to align the reactive epoxide at the thiol of glutathione. This provides new structural insights into the mechanism of LTC4 formation, and also suggests that the observed binding and activation of GSH might be common for a family of homologous proteins important for inflammatory and detoxification responses.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17632546}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17632546 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17632546}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Transmembrane]] | | [[Category: Transmembrane]] |
| [[Category: Trimer]] | | [[Category: Trimer]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 17:30:14 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 14:12:11 2008'' |
