SignificanceTranscriptional coactivators and their partner transcription factors have been labeled as intrinsically disordered, fuzzy, and undruggable. We propose that the identification of conserved mechanisms of engagement between coactivators and their cognate activators should provide general principles for small-molecule modulator discovery. Here, we show that the structurally divergent coactivator Med25 forms short-lived and dynamic complexes with three different transcriptional activators and that conformational shifts are mediated by a flexible substructure of two dynamical helices and flanking loops. Analogous substructures are found across coactivators. Further, targeting one of the flexible structures with a small molecule modulates Med25–activator complexes. Thus, the two conclusions of the work are actionable for the discovery of small-molecule modulators of this functionally important protein class.

Inhibitors of transcriptional protein–protein interactions (PPIs) have high value both as tools and for therapeutic applications. The PPI network mediated by the transcriptional coactivator Med25, for example, regulates stress-response and motility pathways, and dysregulation of the PPI networks contributes to oncogenesis and metastasis. The canonical transcription factor binding sites within Med25 are large (∼900 Å2) and have little topology, and thus, they do not present an array of attractive small-molecule binding sites for inhibitor discovery. Here we demonstrate that the depsidone natural product norstictic acid functions through an alternative binding site to block Med25–transcriptional activator PPIs in vitro and in cell culture. Norstictic acid targets a binding site comprising a highly dynamic loop flanking one canonical binding surface, and in doing so, it both orthosterically and allosterically alters Med25-driven transcription in a patient-derived model of triple-negative breast cancer. These results highlight the potential of Med25 as a therapeutic target as well as the inhibitor discovery opportunities presented by structurally dynamic loops within otherwise challenging proteins.

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In 2008, Lomonaco and Kauffman introduced a knot mosaic system to define a quantum knot system. A quantum knot is used to describe a physical quantum system such as the topology or status of vortexing that occurs on a small scale can not see. Kuriya and Shehab proved that knot mosaic type is a complete invariant of tame knots. In this article, we consider the mosaic number of a knot which is a natural and fundamental knot invariant defined in the knot mosaic system. We determine the mosaic number for all eight-crossing or fewer prime knots. This work is written at an introductory level to encourage other undergraduates to understand and explore this topic. No prior of knot theory is assumed or required.2010 Mathematics Subject Classification. 57M25, 57M27.