PDBsum entry 2uui

Lyase

PDB id: 2uui

Contents

Protein chain

156 a.a. *

Ligands

LMT ×2

PLM ×14

SO4 ×2

Metals

_NI ×3

Waters ×110

* Residue conservation analysis

PDB id:

2uui

Name:

Lyase

Title:

Crystal structure of human leukotriene c4 synthase

Structure:

Leukotriene c4 synthase. Chain: a. Fragment: residues 2-150. Synonym: leukotrienE-C(4) synthase, ltc4 synthase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: pichia pastoris. Expression_system_taxid: 4922.

Resolution:

2.00Å R-factor: 0.198 R-free: 0.237

Authors:

D.Martinez Molina,A.Wetterholm,A.Kohl,A.A.Mccarthy,D.Niegowski, E.Ohlson,T.Hammarberg,S.Eshaghi,J.Z.Haeggstrom,P.Nordlund

Key ref:

D.Martinez Molina et al. (2007). Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase. Nature, 448, 613-616. PubMed id: 17632546 DOI: 10.1038/nature06009

Date:

02-Mar-07 Release date: 17-Jul-07

Protein chain

Q16873  (LTC4S_HUMAN) -  Leukotriene C4 synthase from Homo sapiens

Seq: 150 a.a.

Struc: 156 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: E.C.2.5.1.- - ?????
• Enzyme class 3: E.C.4.4.1.20 - leukotriene-C4 synthase.

Pathway:

• Reaction: leukotriene C4 = leukotriene A4 + glutathione

leukotriene C4 (Bound ligand (Het Group name = PLM) matches with 41.86% similarity) = leukotriene A4 + glutathione (Bound ligand (Het Group name = LMT) matches with 48.72% similarity)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1038/nature06009

Nature 448:613-616 (2007)

PubMed id: 17632546

Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase.

D.Martinez Molina, A.Wetterholm, A.Kohl, A.A.McCarthy, D.Niegowski, E.Ohlson, T.Hammarberg, S.Eshaghi, J.Z.Haeggström, P.Nordlund.

ABSTRACT

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.

Selected figure(s)

Figure 1.
Figure 1: LTC[4] synthase overall structure. a, Left, front view of LTC[4] synthase protomer in ribbon representation showing helices 1–5 in successive colouring. The entire LTC[4] synthase polypeptide, except for the last residue (the last four in the GSH-complexed structure), can be traced in the electron density maps. Right, the homotrimer with protomers coloured orange, green and blue. Bound glutathione, indicating the position of the active site, is in ball and stick representation. Approximate membrane positions indicated by blue lines. b, Cytosolic view of the trimer, showing the position of the three active sites with loop 1 covering each binding pocket. Glutathione is shown in ball and stick representation together with modelled detergent (DDM).

Figure 3.
Figure 3: Glutathione binding. a, Electron density map in blue (F[o] - F[c], contoured at 3 and phased with the apo structure before refinement) for bound glutathione shown in ball and stick representation. Interacting side chains are coloured by monomer and labelled accordingly. Chemical bonds to glutathione are drawn as dashed lines. A coordinated water molecule is shown as a light blue sphere. b, Superposition of the active sites in the apo and glutathione-bound structures in blue and light brown, respectively. Glutathione is shown in orange stick representation and the sulphate molecule from the apo structure in yellow.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2007, 448, 613-616) copyright 2007.

Figures were selected by an automated process.