The importance of G protein-coupled receptors (GPCRs) as drug targets has always been recognized in pharmaceutical industry. One major question for the current GPCR drug discovery is how drugs have distinct efficacies on the same GPCR target. Related to this question, we studied how different ligands can have disparate efficacies to Leukotriene B<sub>4</sub> receptor (BLT2). By using molecular modeling studies, we predicted that TYR271 located at TM6 of BLT2 performs as a key trigger for its activation, and verified the prediction by site-directed mutagenesis, chemotactic motility studies, which included a chemical derivative of agonist CAY10583. We further identified N275 located at TM6 as a weak activation trigger in BLT2 and performed double mutation studies to confirm our computational results. Our results elucidate the exact mechanism of ligand efficacy at BLT2.<br/>

Ligand efficacies at a GPCR: Computational and biochemical studies in the case of leukotriene B4 receptor 2 (BLT2)

256th National Meeting (2018)

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