A novel approach for modulating an important regulator of the unfolded protein response - a cellular process triggered in response to many types of stress that has been implicated in multiple degenerative diseases - is demonstrated in a paper in Nature Chemical Biology this week.
In response to cellular stress, a bifunctional enzyme called IRE1alpha is activated initially via its kinase domain, which in turn leads to the activation of another enzymatic domain called the RNase domain. The latter activity orchestrates the cellular stress response by producing an RNA variant essential for this process. Because of the relationship between the unfolded protein response and human disease, modulators of IRE1alpha's activity could be used to provide insight into the regulation of this important process or as therapeutics.
Previous work has demonstrated that compounds that bind to IRE1alpha’s kinase domain can activate the RNase domain. Dustin Maly, Feroz Papa and colleagues now demonstrate that compounds that bind to this same site in the kinase domain but that induce a distinct conformation can inhibit the activity of the RNase domain.