Abstract
Glucose Regulated Protein 170 (GRP170), also called Oxygen Regulated Protein 150 (ORP150), is a major molecular chaperone resident in the endoplasmic reticulum (ER). It belongs to the heat shock protein (HSP70) super family and can be induced by conditions such as hypoxia, ischemia and interferences in calcium homeostasis. It was recently reported that GRP170 may act as a nucleotide exchange factor (NEF) for GRP78 or binding immunoglobulin protein (BiP), and the ER canonical HSP70. However, little is known about the mechanism underlying its NEF activity. In this study, two homology models of GRP170 were constructed based on the X-ray crystal structures of ADP and ATP bound HSP110, a cytosolic homolog of GRP170, in order to characterize the differences in the binding modes of both ligands. It was observed that the differences in the binding modes of ADP and ATP led to a conformation change in the substrate binding domain which could potentially influence the binding of its substrates such as BiP. Our findings help understand the effect of nucleotide binding on the function of this chaperone protein as a NEF as well as the structural differences between GRP170 and its family members.