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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. October 2003, Volume 2, Number 10, 678-689 |
Modeling of the Anthrax Protective Antigen Binding to the VWA/I Domain of Integrins
Jaya Pandey and David Warburton
Internet Electron. J. Mol. Des. 2003, 2, 678-689
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Abstract:
Anthrax toxin receptor (ATR) is a cell surface receptor that has
been recently recognized as having a homology to Tumor
endothelial marker 8 and human capillary morphogenesis protein
2. Both these proteins have been found to have an extracellular
von Willebrand factor type A domain (VWA), also called
integrin inserted (I) domain. VWA/I domain of the anthrax toxin
receptor is located between AAs 44 and 216 of the extracellular
domain of the receptor. Protective antigen (PA) is the binding
moiety of the anthrax toxin and has been proved to precisely bind
to the VWA/I domain of the toxin receptor. VWA domain/ I
domain of ATR is highly related to VWA/I domain of the
integrins and matrilins. Integrins and matrilins are adhesion
molecules with non-covalently associated alpha and beta
subunits that mediate cell-cell, cell-extracellular matrix,
and cell-pathogen interactions. In order to understand the molecular
interaction of PA to extracellular VWA/I domain of
integrins/ATR, in silico docking of PA was done to the VWA / I
domain of the α-2 integrin. This VWA/I domain is the most
extensively studied domain and also is a homolog of VWA/I
domain of anthrax toxin receptor. Understanding the molecular
interactions between VWA/I domain and protective antigen of
the anthrax toxin is crucial for designing novel therapeutics
targeted to block the binding of the toxin to its cell surface
receptor. BiGGER soft docking algorithm was used for
predicting the interactions between anthrax toxin PA and VWA/I
domain of the integrins. Results were visualized using Chemera
2.0 interface. VEGA open GL1.4.3 software was used for
importing the PDB files for anthrax protective antigen (PDB ID:
1ACC) and VWA/I (PDB ID: 1AOX) domain of α-2 integrin.
Global scoring functions for the first 10 docking solutions were
in the range of 10.43 to 6.5. In the present study the top ranking
solution has been discussed. Results show that PA domain 4 AAs
from I603 to T716 were involved in binding to the VWA/I AAs
V193-T199 and Q215-R243. Also, domain 2 amino acids of PA
from L271 to L450 were also observed to be involved in the
interaction with VWA domain of the integrin. MIDAS site AAs
D151, D153, S155, T221 and D254 were in close vicinity of the
target: probe interface. Lysine at 679 position of PA was
observed to be at the key position in interaction with the VWA
domain. PA residues from K679 to 684 were found to be in
making the close contact with the target (<2.2 Å distance).
Chemical character of the amino acids at the target: probe
recognition site comprised mainly of hydrophobic non-polar
amino acids. The amino acids of domain 2 of protective antigen
were also observed in contact with the VWA/I domain of the
integrin. Domain 2 amino acids are mainly involved in the
transportation of the toxin across the membrane. In the present
study the binding of PA to the VWA/I integrin domain mainly
involved domain 4 and domain 2 of the protective antigen in a
predominantly hydrophobic, nonpolar environment.
AAs K679-K684 of the PA have been speculated to play a significant role in
binding to the VWA/I domain of the receptor. The present study
contributes towards making a framework for future rational
design of anti-receptors/ anti-toxins.
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