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.
Highlights
Gliomas are a heterogenous bunch of tumors which represent thirty percent of the central nervous system tumors
Epigallocatechin gallate (EGCG) docked to full-length Glucose regulated protein 78 (GRP78) with a binding energy of −9.9 kcal/mol for the lowest energy docked structure (Fig. 1)
Molecular docking and molecular dynamics studies using full-length GRP78 in this paper show that binding of EGCG stabilizes the protein faster than the apo state of protein
Summary
Gliomas (including ependymomas, glioblastomas, and oligodendrogliomas) are a heterogenous bunch of tumors which represent thirty percent of the central nervous system tumors. Glucose regulated protein 78 (GRP78), known as Binding Immunoglobulin Protein (BiP) is overexpressed in glioblastoma independent of p53 and PTEN status[6] This protein belongs to HSP70 family of proteins, expressed in endoplasmic reticulum and is a stress-induced protein involved in the Unfolded Protein Response (UPR), for proper folding of the proteins synthesized by the ribosomes[7,8,9]. NBD binds ATP while SBD binds substrate peptide/protein in the form of excluded segment or partially folded protein[12]. These two main domains are connected by an inter domain linker which is highly conserved. Closed conformation is the ADP-bound state, where there is only a little interaction between the two main domains (NBD and SBD)
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