Structural Insights into the Binding Sites of Human B-Arrestin, an Adaptor Protein Involved In GPCR Mediated Apoptosis

Abstract

The present study is aimed at predicting three dimensional (3D) structure of human β- arrestin by homology modeling followed by identifying and characterizing binding sites and there by assessing druggability of the protein. β-arrestins are well-known negative regulators of G-protein-coupled receptor (GPCR) signalling. Based upon PSI-Blast results, 1G4M (PDB ID) was considered as a template for homology modeling. The 3D model was generated with Modeller and further refined using various parameters. The 3D structure was validated using PROCHECK analysis in which acceptable percentage of residues were present in the favoured regions of the Ramachandran Plot. Since there are no co-ordinates of ligand available in template, we used various binding site prediction algorithms to detect different active pockets on the modelled protein. We also tried to correlate the outputs driven from various algorithms. To examine the response of generated model towards various chemical compounds, reported apoptosis inducers were used and docking studies were carried out. The identification of 3D structure, binding sites for various signaling molecules will guide designing molecular tools for therapeutic intervention that may prove useful in numerous disorders associated with β-arrestin- GPCR signaling.