Research in the Mosberg lab focuses primarily on molecular recognition between small to medium size ligands (usually peptides) and their macromolecular targets (usually membrane-associated, G protein-coupled receptors, GPCRs). Key to this research are the determination of structural features of the ligand that favor binding to its target (and only its target), which requires the design, synthesis, and pharmacological evaluation of new ligands, and the elucidation of the bioactive conformation (pharmacophore) of the ligand. This entails first the development of a relatively inflexible ligand and, then, its conformational evaluation via NMR, x-ray, and/or computational methods.
Clearly, structural studies on the target proteins are necessary to complete the molecular recognition picture. Since GPCRs, like other membrane proteins, present crystallization problems, we have developed modeling approaches to predict GPCR structures. This has proven to be extremely effective and has allowed the development of precise, detailed models of ligand-receptor interactions. Testing of these models is also done in our group. The approach is one that combines site directed mutagenesis of the receptor with the design of complementary ‘rescue mutations’ of the ligand. That is, the ligand is modified such that it will bind favorably with the mutant receptor but not the wild type.
Finally, our research interests are not confined to the function of membrane proteins. We are also pursuing projects aimed at developing small molecule (peptide) inhibitors of interactions between soluble proteins. Our approach is one of structure-based design in which an initial experimental structure encompassing the protein-protein interaction surface can be used as the basis for inhibitor design.
- 2004 Fellow, in the American Association for the Advancement of Science, American Association for the Advancement of Science