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Search The CSA
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Catalytic Site Atlas

CSA LITERATURE entry for 1pwv

E.C. nameanthrax lethal factor endopeptidase
SpeciesBacillus anthracis ()
E.C. Number (IntEnz) 3.4.24.83
CSA Homologues of 1pwv1j7n,1jky,1pwp,1pwq,1pwu,1pww,1yqy,1zxv,
CSA Entries With UniProtID P15917
CSA Entries With EC Number 3.4.24.83
PDBe Entry 1pwv
PDBSum Entry 1pwv
MACiE Entry 1pwv

Literature Report

IntroductionLethal Factor is critical in anthrax pathogenesis, by acting as a specific protease cleaving members of the MAPKK (mitogen-activated protein kinase kinase) family at their amino termini. This results in signalling pathway inhibition. The catalytic domain of this enzyme is distantly related to the zinc metalloprotease family.
The implications of finding targets for inhibition of anthrax lethal factor are obvious and so the catalytic details of this enzyme should be highly important.
MechansimThe active site is centred around a structural zinc cation coordinated by a strictly conserved HExxH+E motif. The zinc ion is directly coordinated by the two histidines of the motif, by Glu 735 and by a water molecule which forms a strong hydrogen bonding interaction with the Glu of the motif and with the conserved Tyr 728. Glu 687 acts as a general base to activate the water molecule for nucleophilic attack. Tyr 728, in addition to coordinating the catalytic water, stabilises the amino group of the leaving amino acid, causing a displacement of partial electrostatic charges that weaken the peptide bond, rendering it more susceptible to the nucleophilic attack of the water molecule. It acts as a general base to facilitate protonation of the leaving amino group.
Reaction

Catalytic Sites for 1pwv

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluA687720macie:sideChainActs as a general base to activate the zinc-bound water during catalysis.
TyrA728761macie:sideChainActs as a general base to facilitate protonation of the leaving amino group. Also coordinates and stabilises the leaving group and the water molecule.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluB687720macie:sideChainActs as a general base to activate the zinc-bound water during catalysis.
TyrB728761macie:sideChainActs as a general base to facilitate protonation of the leaving amino group. Also coordinates and stabilises the leaving group and the water molecule.

Literature References

Notes:Zinc is also an essential bound group required for catalysis, evidence is given in the paper of PubMed ID 14672720.
Pannifer AD
Crystal structure of the anthrax lethal factor.
Nature 2001 414 229-233
PubMed: 11700563
Hammond SE
Lethal factor active-site mutations affect catalytic activity in vitro.
Infect Immun 1998 66 2374-2378
PubMed: 9573135
Charlton HM
The effect of mating upon LH release in male and female voles of the species Microtus agrestis.
J Reprod Fertil 1975 42 167-170
PubMed: 1110468
Tonello F
Tyrosine-728 and glutamic acid-735 are essential for the metalloproteolytic activity of the lethal factor of Bacillus anthracis.
Biochem Biophys Res Commun 2004 313 496-502
PubMed: 14697216
Kim J
Implication of pH in the catalytic properties of anthrax lethal factor.
Biochem Biophys Res Commun 2004 313 217-222
PubMed: 14672720
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