Heat shock protein 90-Cell division cycle 37-Prostaglandin E synthase 3 complex (Hsp90-Cdc37-p23) (Hsp90-Cdc37-p23)

The Heat shock protein 90-Cell division cycle 37-Prostaglandin E synthase 3 complex (Hsp90-Cdc37-p23) is a specialized molecular chaperone assembly essential for the maturation and stabilization of numerous client proteins, particularly oncogenic kinases (Verba et al., 2016, PMID: 27050101). Heat shock protein 90 (Hsp90) serves as the central scaffold, while Cdc37 acts as a kinase-specific co-chaperone that delivers client kinases to the Hsp90 machinery (Pearl, 2005, PMID: 16226698). The p23 co-chaperone (also known as Prostaglandin E synthase 3 or PTGES3) subsequently binds to the ATP-bound state of Hsp90, stabilizing the closed conformation of the complex and facilitating the final stages of protein folding (Johnson & Toft, 1994, PMID: 7935439). This complex is frequently overexpressed or hijacked in cancer cells to maintain the stability of mutated or overexpressed signaling proteins like HER2, Akt, and Raf-1, which drive uncontrolled proliferation (Neckers & Workman, 2012, PMID: 22437103). Consequently, the complex is a high-priority therapeutic target; inhibiting its components leads to the ubiquitin-mediated degradation of client proteins (Schopf et al., 2017, PMID: 28429788). Therapeutic strategies include small molecules that compete with ATP binding on Hsp90 or disrupt the protein-protein interactions between Hsp90 and its co-chaperones (Taipale et al., 2010, PMID: 20539337). Despite clinical potential, challenges such as off-target toxicities and the induction of a compensatory heat shock response remain significant hurdles in drug development (Butler et al., 2015, PMID: 25813490).

Other names

Hsp90-Cdc37-p23 complexHsp90-Cdc37-PTGES3 complexHsp90-Cdc37-p23 chaperone complexHsp90-Cdc37-p23 heterocomplexHsp90–Cdc37/p23 complex

Competitive inhibition of the Hsp90 N-terminal ATP-binding site, preventing the conformational changes required for client protein maturation; disruption of the Cdc37-Hsp90 interface to prevent kinase recruitment; inhibition of p23 binding to stabilize the Hsp90-client complex in a non-functional state; induction of ubiquitin-proteasome mediated degradation of client proteins.