2uui

From Proteopedia

Revision as of 18:06, 18 December 2007

CRYSTAL STRUCTURE OF HUMAN LEUKOTRIENE C4 SYNTHASE

Overview

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.

Disease

Known disease associated with this structure: Leukotriene C4 synthase deficiency OMIM:[246530]

About this Structure

2UUI is a Single protein structure of sequence from Homo sapiens with NI, SO4, LMT and PLM as ligands. Active as Leukotriene-C(4) synthase, with EC number 4.4.1.20 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase., Molina DM, Wetterholm A, Kohl A, McCarthy AA, Niegowski D, Ohlson E, Hammarberg T, Eshaghi S, Haeggstrom JZ, Nordlund P, Nature. 2007 Aug 2;448(7153):613-6. Epub 2007 Jul 15. PMID:17632546

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