Norstictic acid is a selective allosteric transcriptional regulator

Garlick, J. M.; Sturlis, S. M.; Bruno, P. A.; Yates, J. A.; Peiffer, A.; Liu, Y.; Goo, L.; Bao, L.; De Salle, S.; Tamayo-Castillo, G.; Brooks, C. L.; Merajver, S. D.; Mapp, A. K.

doi:10.1101/2021.03.26.437253

bioRxiv · 10.1101/2021.03.26.437253

Norstictic acid is a selective allosteric transcriptional regulator

Garlick, J. M.·Sturlis, S. M.·Bruno, P. A.·Yates, J. A.·Peiffer, A.·Liu, Y.·Goo, L.·Bao, L.·De Salle, S.·Tamayo-Castillo, G.·Brooks, C. L.·Merajver, S. D.·Mapp, A. K.

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Abstract

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 [A]2) and have little topology, and thus 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 comprised of 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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Garlick, J. M., Sturlis, S. M., Bruno, P. A., Yates, J. A., Peiffer, A., Liu, Y., Goo, L., Bao, L., De Salle, S., Tamayo-Castillo, G., Brooks, C. L., Merajver, S. D., Mapp, A. K.. 2021-03-26. Norstictic acid is a selective allosteric transcriptional regulator. https://doi.org/10.1101/2021.03.26.437253

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