Abstract
Glucose-regulated protein 78 (GRP78), is overexpressed in glioblastoma, other tumors and during viral and bacterial infections, and so, it is postulated to be a key drug target. EGCG, an ATP-competitive natural inhibitor, inhibits GRP78 effect in glioblastoma. Structural basis of its action on GRP78 nucleotide-binding domain and selectivity has been investigated. We were interested in exploring the large-scale conformational movements travelling to substrate-binding domain via linker region. Conformational effects of EGCG inhibitor as well as ATP on full length GRP78 protein were studied using powerful MD simulations. Binding of EGCG decreases mobility of residues in SBDα lid region as compared to ATP-bound state and similar to apo state. The decreased mobility may prevent its opening and closing over SBDβ. This hindrance to SBDα subdomain movement, in turn, may reduce the binding of substrate peptide to SBDβ. EGCG binding folds the protein stably as opposed to ATP binding. Several results from EGCG binding simulations are similar to that of the apo state. Key insights from these results reveal that after EGCG binding upon competitive inhibition with ATP, GRP78 conformation may revert to that of inactive, apo state. Further, SBD may adopt a semi-open conformation unable to facilitate association of substrates.