Heat shock protein 90 N-terminal domain (HSP90 NTD) (HSP90 NTD)

The Heat shock protein 90 (HSP90) N-terminal domain is a highly conserved region of the HSP90 molecular chaperone that contains the essential ATP-binding pocket [1, 2]. This domain is responsible for the ATPase activity that drives the conformational changes necessary for the chaperone's function in protein folding and stabilization [1, 6, 10]. HSP90 facilitates the maturation of hundreds of "client" proteins, including many oncoproteins involved in cell signaling, cell cycle regulation, and apoptosis [2, 3, 11]. In cancer cells, HSP90 is often overexpressed and hijacked to maintain the stability of mutated or overexpressed signaling proteins, a phenomenon known as oncogene addiction [3, 11]. Therapeutic targeting of the N-terminal domain involves small molecules that competitively bind to the ATP pocket, thereby inhibiting the chaperone cycle [1, 2, 10]. This inhibition leads to the misfolding and subsequent proteasomal degradation of client proteins, resulting in the simultaneous disruption of multiple oncogenic pathways [2, 3, 10, 12]. While potent in preclinical models, N-terminal inhibitors have faced clinical hurdles such as hepatotoxicity, ocular toxicity, and the induction of a pro-survival heat shock response [2, 7, 12, 14].

Other names

HSP90 amino-terminal domainHSP90 ATP-binding domainN-terminal domain of Heat shock protein 90HSP90 NTD

Competitive inhibition of the ATP-binding pocket in the N-terminal domain [1, 2, 10], preventing the ATPase-driven chaperone cycle [1, 6, 10] and leading to the proteasomal degradation of client proteins [2, 3, 10, 12].