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

The Heat shock protein 90 (HSP90) N-terminal ATPase domain is a highly conserved structural region of the HSP90 molecular chaperone, characterized by a unique Bergerat fold belonging to the GHKL ATPase superfamily [1.2.1, 1.4.3]. This domain is responsible for binding and hydrolyzing ATP, which provides the energy required for the chaperone's conformational cycle, transitioning from an "open" to a "closed" state to facilitate the maturation of client proteins [1.1.1, 1.3.1]. HSP90 regulates over 400 client proteins, including critical signaling kinases, steroid hormone receptors, and transcription factors that are often mutated or overexpressed in cancer [1.3.1, 1.5.2]. In malignant cells, HSP90 is frequently found in a high-affinity multi-chaperone complex that stabilizes these oncoproteins, a state referred to as oncogene addiction [1.4.2, 1.4.4]. Therapeutic agents targeting this domain, such as tanespimycin and ganetespib, act as competitive inhibitors of the ATP-binding pocket, thereby stalling the chaperone cycle and triggering the degradation of client proteins through the ubiquitin-proteasome pathway [1.3.2, 1.4.4]. Despite significant clinical interest, the development of N-terminal inhibitors has been limited by dose-limiting toxicities, including hepatotoxicity and ocular disturbances, as well as the induction of a compensatory heat shock response [1.5.1, 1.5.2].

Other names

HSP90 N-terminal domainHSP90 NTDN-terminal domain of Heat shock protein 90ATP-binding domain of Heat shock protein 90N-terminal nucleotide-binding domain of HSP90HSP90 N-terminal ATPase domain

Competitive inhibition of the N-terminal ATP-binding pocket, preventing ATP binding and hydrolysis, which disrupts the chaperone cycle and leads to the degradation of client proteins via the ubiquitin-proteasome pathway.