Insights into the anthrax lethal factor-substrate interaction and selectivity using docking and molecular dynamics simulations.
Protein Sci
; 18(8): 1774-85, 2009 Aug.
Article
en En
| MEDLINE
| ID: mdl-19585464
ABSTRACT
The anthrax toxin of the bacterium Bacillus anthracis consists of three distinct proteins, one of which is the anthrax lethal factor (LF). LF is a gluzincin Zn-dependent, highly specific metalloprotease with a molecular mass of approximately 90 kDa that cleaves most isoforms of the family of mitogen-activated protein kinase kinases (MEKs/MKKs) close to their amino termini, resulting in the inhibition of one or more signaling pathways. Previous studies on the crystal structures of uncomplexed LF and LF complexed with the substrate MEK2 or a MKK-based synthetic peptide provided structure-activity correlations and the basis for the rational design of efficient inhibitors. However, in the crystallographic structures, the substrate peptide was not properly oriented in the active site because of the absence of the catalytic zinc atom. In the current study, docking and molecular dynamics calculations were employed to examine the LF-MEK/MKK interaction along the catalytic channel up to a distance of 20 A from the zinc atom. This residue-specific view of the enzyme-substrate interaction provides valuable information about (i) the substrate selectivity of LF and its inactivation of MEKs/MKKs (an issue highly important not only to anthrax infection but also to the pathogenesis of cancer), and (ii) the discovery of new, previously unexploited, hot-spots of the LF catalytic channel that are important in the enzyme/substrate binding and interaction.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
3_ND
Problema de salud:
3_neglected_diseases
/
3_zoonosis
Asunto principal:
Bacillus anthracis
/
Toxinas Bacterianas
/
Quinasas de Proteína Quinasa Activadas por Mitógenos
/
Antígenos Bacterianos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Protein Sci
Asunto de la revista:
BIOQUIMICA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Grecia