78 kDa glucose-regulated protein (GRP78) ATPase domain (GRP78)

The 78 kDa glucose-regulated protein (GRP78) ATPase domain is the N-terminal nucleotide-binding domain (NBD) of the GRP78 chaperone, which is responsible for binding and hydrolyzing ATP (UniProt P11021). This enzymatic activity is crucial for the chaperone's function, as it regulates the affinity of the C-terminal substrate-binding domain for unfolded proteins (PubMed: 33414238). GRP78 is a central regulator of endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR), and its overexpression is a hallmark of many cancers, where it facilitates tumor growth and drug resistance (PubMed: 24614304). Because the ATPase domain controls the functional cycle of the protein, it has become a primary target for small-molecule inhibitors like HA15 and YUM70, which aim to block GRP78 activity and trigger apoptosis in cancer cells (PubMed: 27292635). Beyond oncology, the GRP78 ATPase domain is investigated in the context of viral infections and neurodegenerative diseases where ER stress plays a pivotal role (PubMed: 32406758).

Other names

Binding immunoglobulin protein (BiP)Heat shock protein family A member 5 (HSPA5)Endoplasmic reticulum lumenal Ca(2+)-binding protein grp7878 kDa glucose-regulated protein N-terminal domain

Inhibition of ATPase activity through competitive or allosteric binding to the N-terminal nucleotide-binding domain, which prevents the conformational changes required for chaperone-mediated protein folding and triggers ER stress-mediated apoptosis.