Multi-Pole Approach to Structural Science

May 10 - 13, 2015

Structural biology aspects of ligand directed signaling in G-protein coupled receptors
Krzysztof Jozwiak, Karolina Pajak, Anita Plazinska, Irving W. Wainer

Biased agonism (a.k.a. ligand directed signaling) emerges as one of the most promising approach in design, discovery and development of new medicinal compounds targeting G-protein coupled receptors (GPCRs) in future therapies. Most GPCRs induce a myriad of intracellular signaling responses upon activation (e.g., G –protein coupling, beta-arrestin recruitment) and recent discoveries strongly suggest that different ligands may stimulate one or the other response in a selective manner. A lot of examples of ligands acting on various GPCRs for which biased effects has been reported; RCSB Protein Data Bank contains a growing number of crystal structures for various GPCRs. However, relatively little is known on structural basis of ligand directed signaling on molecular levels. Current presentation will review structural aspects of ligand directed signaling in GPCRs. Structural chemistry analyses allow in some cases to define molecular requirements for a ligand to evoke signaling biased between G protein and beta-arrestin pathways. Our study of newly developed beta2-adrenergic receptor agonists reveals that biased agonism manifested by the fact that some derivatives activate the receptor to couple exclusively the Gs protein is linked to specific interaction of a ligand with Y308 residue of the receptor. The interaction most likely interferes the conformational transition toward the active state and therefore may be responsible for selective recognition of Gs protein by the intracellular domain. The mechanism seems to be uniform for GPCR family as similar observation has been made for D2L-dopaminergic or M2-muscarinic receptor.