GRP78 is a member of the heat shock protein family. At stressful conditions GRP78 increases of its expression level and the presence of a surface membrane-bound form of GRP78. It has been demonstrated that this over expression of GRP78 is linked to a greater degree of malignancy in cancer cells. In addition, GRP78 induction has been correlated with the development of resistance to various cytotoxic agents. The structure of GRP78 is not yet known. EGCG is a major component in green tea, and its inhibitory activity against tumor genesis has been shown. To understand the underlying mechanism of how EGCG inhibits the activation of GRP78 by ATP, a homology model of N-Terminal domain of GRP78 was carried out based on the already solved X-ray structure of ATPase domain of human Heat Shock Protein 70 (hHSP70) (PDBid:1S3X), a highly homologous protein from the same super family of proteins. Based on the homology model, it was first hypothesized and later confirmed by our laboratory (ref 1) through competitive binding experiments between EGCG and ATP with GRP78 that EGCG binds to the ATP binding site in the N-Terminal domain of GRP78. To further understand how EGCG binds to GRP78, docking studies were carried out using both Glide (Schrodinger, LLC) and CAChe (Fujitsu, Inc). Based on the resultant binding confirmations from these studies, it was found that the mode of binding of EGCG involves in a network of hydrogen bonding interactions and interaction with various charged residues within the GRP78 ATP binding site.

1. Ermakova, S.P., B. S. Kang, B. Y. Choi, H. S. Choi, T. F. Schuster, W. Y. Ma, A. M. Bode, and Z. Dong. (-)-Epigallocatechin Gallate Overcomes Resistance to Etoposide-Induced Cell Death by Targeting the Molecular Chaperone Glucose-Regulated Protein 78. 2006. Cancer Research. 66:9260-9269.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA