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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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