| 1PWV |
Hydrolase |
date |
Jul 02, 2003  |
|---|
| title | Crystal Structure Of Anthrax Lethal Factor Wild-Type Protein Complexed With An Optimised Peptide Substrate. |
| authors | T.Y.Wong, R.Schwarzenbacher, R.C.Liddington |
| compound |
source |
Molecule: Lethal Factor
Chain: A, B
Synonym: Lf, Anthrax Lethal Toxin Endopeptidase Component
Ec: 3.4.24.-
Engineered: Yes
|
Organism_scientific: Bacillus Anthracis
Gene: Lef Or Pxo1-107
Expression_system: Bacillus Anthracis
Expression_system_strain: Bh441
Expression_system_vector_type: Plasmid
Expression_system_plasmid: Px01
|
Molecule: Lf20
Chain: C, D
Engineered: Yes
|
Synthetic: Yes
Other_details: This Optimised Peptide Substrate Was Synthesised.
|
| symmetry | Space Group: P 1 21 1
| R_factor | 0.231 |
crystal
cell |
| length a |
length b |
length c |
angle alpha |
angle beta |
angle gamma |
| 96.700 |
137.400 |
98.300 |
90.00 |
98.00 |
90.00 |
|
| method | X-Ray Diffraction | resolution | 2.85 Å |
| ligand |
| enzyme | Hydrolase
E.C.3.4.24
BRENDA
|
| domain | The pa-binding region is found in both b.anthracis ef and lf. Domain iv contains the catalytic center. It comprises four domains translocating component (pa); domains ii, iii and iv together create a long deep groove that holds the 16-residue n-terminal tail of mapkk before cleavage. |
| similarity | Belongs to the peptidase m34 family.[ATLF] |
| subunit | Anthrax toxins are composed of three distinct proteins, a protective antigen (pa), a lethal factor (lf) and an edema factor (ef). None of these is toxic by itself. Pa+lf forms the lethal toxin (letx); pa+ef forms the edema toxin (edtx). |
| catalytic activ. | The only known protein substrates are mitogen-activated protein (map) kinase kinases. Preferred amino acids around the cleavage site can be denoted bbbbxhx-|-h, in which b denotes arg or lys, h denotes a hydrophobic amino acid, and x is any amino acid. |
| induction | Positively transcriptionally regulated by atxa, which, in turn, is induced by bicarbonate and high temperatures (37 degrees celsius). |
| subcellular loc. | Secreted protein. |
| genes | BXA0172, GBAA, lef (B. anthracis) |
| function | Lf is not toxic by itself. It is a protease that cleaves the n-terminal of most dual specificity mitogen-activated protein kinase kinases (mapkks or map2ks) (except for map2k5). One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. Cleavage invariably occurs within the n-terminal proline-rich region preceding the kinase domain, thus disrupting a sequence involved in directing specific protein-protein interactions necessary for the assembly of signaling complexes. There may be other cytosolic targets of lf involved in cytotoxicity. Lf is the lethal factor that, when associated with pa, causes death. The proteasome may mediate a toxic process initiated by lf in the cell cytosol involving degradation of unidentified molecules that are essential for macrophage homeostasis. This is an early step in letx intoxication, but it is downstream of the cleavage by lf of mek1 or other putative substrates. |
Gene
Ontology | |
| Primary reference | The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor., Turk BE, Wong TY, Schwarzenbacher R, Jarrell ET, Leppla SH, Collier RJ, Liddington RC, Cantley LC, Nat Struct Mol Biol 2004 Jan;11(1):60-6. Epub 2003 Dec 29. PMID:14718924 |
