Protein homeostasis is one of the key mechanisms that determine cellular life, and the Hsp90 family of molecular chaperones plays a key role in it. While Hsp90 dysregulation is a hallmark of numerous diseases, ranging from cancer to neurodegeneration, traditional inhibitors targeting its highly conserved ATPase site have largely failed in the clinic due to off-target toxicity and compensatory stress responses. One of the challenges in drug discovery, as well as in the development of chemical tools to investigate the specific roles of single family members, lies in achieving isoform specificity across the cytoplasm, ER, and mitochondria. Here, we exploit the intrinsic asymmetry of mitochondrial isoform TRAP1 and combine it with a fragment-design inspired approach to develop new possible TRAP1 targeting leads. We start from the consideration that TRAP1 catalytic cycle relies on a strained, asymmetric dimer conformation that enforces sequential ATP hydrolysis. By integrating advanced computational dynamics with biochemical profiling, we demonstrate that small molecules can be rationally designed to target these transient asymmetric states. Our findings reveal that targeting allosteric, symmetry-breaking interfaces allows for the modulation of TRAP1, offering a novel platform and starting point for next-generation, isoform-specific anticancer therapeutics.
Guarra et al. (Sun,) studied this question.