Heat shock protein 90 alpha C-terminal domain (HSP90α CTD) (HSP90α CTD)

Heat shock protein 90 alpha (HSP90α) is a highly conserved molecular chaperone essential for the folding, stability, and maturation of numerous client proteins, many of which are key drivers in oncogenesis and signal transduction (UniProt P07900). The C-terminal domain (CTD) of HSP90α is critical for the protein's constitutive dimerization and contains a cryptic ATP-binding pocket that regulates the chaperone cycle (PubMed: 15546861). Unlike N-terminal domain (NTD) inhibitors, which often trigger a compensatory heat shock response (HSR) that limits efficacy and increases toxicity, CTD inhibitors disrupt chaperone function without inducing HSR (PubMed: 26153783). This makes the HSP90α CTD an attractive therapeutic target for treating various cancers and neurodegenerative disorders by promoting the degradation of misfolded or overexpressed proteins (PubMed: 22107490). Current research focuses on developing small molecules that bind this site to selectively inhibit the chaperone's activity while avoiding the pitfalls of first-generation HSP90 inhibitors (PubMed: 19413328).

Other names

HSP90AA1 C-terminal domainHsp90 alpha CTDC-terminal ATP-binding site of HSP90Hsp90 dimerization domain

Allosteric inhibition of the C-terminal ATP-binding site, which prevents the conformational changes necessary for the chaperone cycle and disrupts the dimerization of HSP90 subunits, leading to the proteasomal degradation of client proteins without inducing the heat shock response (PubMed: 26153783, PubMed: 15546861).