Open AccessNorstictic Acid Is a Selective Allosteric Transcriptional Regulator
Author(s) -
Julie M. Garlick,
Steven Sturlis,
Paul A. Bruno,
Joel A. Yates,
Amanda L. Peiffer,
Yejun Liu,
Laura Goo,
Liwei Bao,
Samantha N. De Salle,
Giselle TamayoCastillo,
Charles L. Brooks,
Sofía D. Merajver,
Anna K. Mapp
Publication year - 2021
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.1c03258
Subject(s) - chemistry , allosteric regulation , coactivator , regulator , transcription factor , activator (genetics) , transcriptional regulation , small molecule , binding site , computational biology , microbiology and biotechnology , biochemistry , cancer research , biology , enzyme , gene
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 Å 2 ) 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.