Organic Chemistry Seminar: Dr. Jaron Mercer, Broad Institute of Harvard and MIT
Jaron Mercer
About the Seminar
Synthesis of the ladderane lipids and continuous evolution of proteins that bind small molecules
The ladderane lipids are natural membrane phospholipids with unusual polycyclobutane motifs from anaerobic ammonium oxidizing (anammox) bacteria. I will share our synthetic approach to both [5]- and [3]-ladderane lipid tails and their assembly into phospholipids. We showed that ladderane phospholipids form dense but fluid membranes with low permeability to protons, likely a specific adaptation to preserve the delicate proton motive force from anammox catabolism.
In medicinal chemistry, we modify a chemical scaffold to improve binding affinity for a target protein. The reverse is also possible: mutations to a protein can improve binding affinity for a target small molecule. Bespoke small-molecule-binding proteins have applications in targeted protein degradation, biosensing, and therapeutic drug reversal, but they are generally tedious to produce. We use phage-assisted continuous evolution to rapidly perform ligand-specific affinity maturation, both for small molecules that cooperatively bridge two proteins (molecular glues) and standalone ligands. I will describe the evolution of small degron tags that bind E3 ligase effector cereblon in complex with highly specific molecular glues and our efforts to mature designed small-molecule-binding proteins in an automated culture system.
About the Speaker
Jaron Mercer is an NIH postdoctoral fellow in Professor David Liu's group at the Broad Institute of Harvard and MIT. He grew up in San Diego, CA and attended Harvard College for his bachelor's degree in chemistry, conducting research with Prof. Andrew Myers. Jaron's graduate studies were in organic chemistry with Prof. Noah Burns at Stanford University, where he developed a total synthesis of the polycyclobutane-containing ladderane lipids. His current research bridges organic synthesis and molecular biology to build tools for the continuous directed evolution of proteins that bind small-molecule ligands.