Talk given by Tom Sakmar (The Rockefeller University, USA) as part of the International GCE Webinar series. Live talk given on February 15th, 2024.
Novel methods, including the genetic encoding of unnatural amino acids in mammalian expression systems, have been developed to probe visual pigments, G protein-coupled re-ceptors, channels and other difficult-to-express membrane proteins. A variety of ancillary experimental chemical biology approaches have been adapted recently in the Sakmar la-boratory, including targeted photo-crosslinking to map ligand and antibody binding sites, and bioorthogonal labeling reactions to introduce site-specific fluorophores, monoclonal antibody epitopes to facilitate single molecule imaging studies, and drug fragments to fa-cilitate fragment-based drug screening. These strategies can be used in combination with traditional biochemical and biophysical approaches to enhance drug discovery efforts. This lecture will address recently developed experimental approaches to discover and probe “cryptic” ligand-binding sites in GPCRs using a combination of unnatural amino acid mutagenesis, molecular dynamics simulations and medicinal chemistry to create “clicka-ble” drug analogues.