Organizers: Brent Stockwell, Columbia University; and Tarun Kapoor, The Rockefeller University
Small molecules offer a powerful means of probing biological systems because they provide temporal control of protein function. This meeting of the Chemical Biology Discussion Group will offer an overview of current topics in this field of chemical biology. Presentations will focus on new chemical tools and their use to study specific biological systems. The gathering will feature a keynote address by Jack Taunton from UCSF and short talks by leading postdocs and graduate students from the greater NY area who have been selected by the organizing committee.
Keynote Speaker: Jack Taunton, University of California, San Francisco, "Chemical Inhibitors of Signaling and Secretion: Intelligent Design vs. Natural Selection."
"Chemical Inhibitors of Signaling and Secretion: Intelligent Design vs. Natural Selection."
I will tell two stories, both of which show how synthetic chemistry can illuminate the inner workings of mammalian cells. First, we have devised a structural bioinformatics approach to design highly specific protein kinase inhibitors. There are ~500 protein kinases in the human genome, and their structural similarity makes the design of selective inhibitors a formidable challenge. One of our inhibitors specifically inactivates RSK, a protein kinase in the RAS signaling pathway whose functions are poorly understood. Second, we have dissected the molecular mechanism of a natural product that blocks the expression of certain secreted proteins. Amazingly, this cyclic peptide prevents signal sequence-dependent gating of the Sec61 protein-conducting channel and thereby blocks the translocation of select proteins into the endoplasmic reticulum.
"Small-Molecule Inhibition of Siderophore Biosynthesis in Mycobacterium tuberculosis and Yersinia pestis."
Mycobacterium tuberculosis and Yersinia pestis, the causative agent of tuberculosis and the etiologic agent of plague, respectively, both have iron acquisition systems based on siderophores, secreted iron-chelating compounds with extremely high Fe3+ affinity. Several lines of evidence suggest that siderophores play a critical role in bacterial iron acquisition inside the human host, where the free iron concentration is well below that required for the bacterial growth and virulence. Thus, siderophore biosynthesis is an attractive target for the development of new antibiotics to treat tuberculosis and plague. We report the design, synthesis, and biological evaluation of a mechanism-based inhibitor of domain salicylation enzymes required for sidero