Molecular Signature of Biased Agonism in G-protein Coupled Receptors

Molecular Signature of Biased Agonism in G-protein Coupled Receptors Molecular Signature of Biased Agonism in G-protein Coupled Receptors Historically, G-protein-coupled receptors (GPCRs) were regarded as bimodal switches whereby the binding of an agonist causes a conformational change in the receptor structure, shifting the receptor equilibrium from a predominantly inactive to an active state. However, it is now apparent that some ligands can stabilize distinct receptor conformations and thus lead to different functional outcomes. This observation is known as bias. Through rational mutagenesis, Lilly San Diego has engineered mutations in the Mu Opioid Receptor (MOR) that locks the receptor in the G-protein biased active state. The innovative stabilized mutants can be further explored for the structural studies of GPCR biased state. To date, no structure of GPCR at the biased active state has been reported. Currently, there are approximately 30 GPCR crystal structures available in the Protein Data Bank (PDB), mostly solved using the lipidic cubic phase (LCP) technology; none of these, however, are in the G-protein biased conformational state. GPCRs represent 50-60% of the current drug targets. A deeper understanding of the molecular signature of GPCR biased agonism will bolster Lillys capability to drive GPCR structure activity relationship (SAR) to design safer, more potent and efficacious GPCR ligands.