2uui
From Proteopedia
| Line 4: | Line 4: | ||
|PDB= 2uui |SIZE=350|CAPTION= <scene name='initialview01'>2uui</scene>, resolution 2.00Å | |PDB= 2uui |SIZE=350|CAPTION= <scene name='initialview01'>2uui</scene>, resolution 2.00Å | ||
|SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:So4+Binding+Site+For+Chain+A'>AC1</scene> | ||
| - | |LIGAND= <scene name='pdbligand= | + | |LIGAND= <scene name='pdbligand=LMT:DODECYL-BETA-D-MALTOSIDE'>LMT</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene>, <scene name='pdbligand=PLM:PALMITIC+ACID'>PLM</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Leukotriene-C(4)_synthase Leukotriene-C(4) synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.4.1.20 4.4.1.20] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Leukotriene-C(4)_synthase Leukotriene-C(4) synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.4.1.20 4.4.1.20] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[2uuh|2UUH]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2uui FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2uui OCA], [http://www.ebi.ac.uk/pdbsum/2uui PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2uui RCSB]</span> | ||
}} | }} | ||
| Line 14: | Line 17: | ||
==Overview== | ==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. | 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:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=246530 246530]] | ||
==About this Structure== | ==About this Structure== | ||
| Line 36: | Line 36: | ||
[[Category: Ohlson, E.]] | [[Category: Ohlson, E.]] | ||
[[Category: Wetterholm, A.]] | [[Category: Wetterholm, A.]] | ||
| - | [[Category: LMT]] | ||
| - | [[Category: NI]] | ||
| - | [[Category: PLM]] | ||
| - | [[Category: SO4]] | ||
[[Category: apo]] | [[Category: apo]] | ||
[[Category: eicosanoid]] | [[Category: eicosanoid]] | ||
| Line 54: | Line 50: | ||
[[Category: trimer]] | [[Category: trimer]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:04:37 2008'' |
Revision as of 02:04, 31 March 2008
| |||||||
| , resolution 2.00Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | , , , | ||||||
| Activity: | Leukotriene-C(4) synthase, with EC number 4.4.1.20 | ||||||
| Related: | 2UUH
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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.
About this Structure
2UUI is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase., Martinez Molina D, 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
Page seeded by OCA on Mon Mar 31 05:04:37 2008
Categories: Homo sapiens | Leukotriene-C(4) synthase | Single protein | Eshaghi, S. | Haeggstrom, J Z. | Hammarberg, T. | Kohl, A. | Mccarthy, A A. | Molina, D Martinez. | Niegowski, D. | Nordlund, P. | Ohlson, E. | Wetterholm, A. | Apo | Eicosanoid | Enzyme | Human | Leukotriene biosynthesis | Leukotriene signalling | Ltc4 | Lyase | Mapeg | Membrane | Membrane protein | Transmembrane | Trimer
