Organic Chemistry Seminar: Professor Anna Mapp, University of Michigan (Host: Steven Banik)
About the Seminar
"Writing the Rules for Targeting Dynamic Transcriptional Coactivators with Small Molecules"
Transcriptional 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. Towards that end, biophysical characterization of the structurally divergent coactivator Med25 reveals that it 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 eukaryotic 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.
About the Speaker
Anna K. Mapp is the Edwin Vedejs Collegiate Professor of Chemistry and a Research Professor of the Life Sciences Institute at the University of Michigan. She is also the Associate Dean of Biological & Health Sciences at Rackham Graduate School, University of Michigan. She received an A.B. in Chemistry from Bryn Mawr College and the Ph.D. in Organic Chemistry from University of California-Berkeley. Following a postdoctoral fellowship at Caltech, she began her independent career at the University of Michigan. Mapp’s research interests center around the conformationally dynamic protein complexes that are central to gene activation. More specifically, her group uses multidisciplinary strategies to define the molecular recognition framework of transcriptional coactivator-transcription factor complexes and to use the framework to target the complexes for therapeutic purposes. She has received a number of awards for her work, including election to the American Academy of Arts & Sciences, the Harold R Johnson Diversity Service Award, and the Emil T. Kaiser Award. Outside of the University of Michigan Mapp serves as an Associate Editor of the journal ACS Chemical Biology, a member of the Basic Science Council of the National Cancer Institute, a member of the Scientific Advisory Board of the Max Planck Institute of Chemical Ecology, and an organizer of PACIFICHEM 2021.
Photo courtesy of Leisa Thompson.