Biased agonism is a term describing the phenomenon that G protein-coupled receptors (GPCRs) are highly dynamic proteins. It can adopt numerous ligand-specific conformational ensembles with distinct impact on signaling and regulatory profiles, even with ligands acting via a common binding pocket.

The N-terminal and the residues on transmembrane loop 1 (TM1) near the extracellular domain of glucagon-like peptide-1 receptor, a member of the glucagon receptor subfamily of class B GPCR, are very flexible and usually missing in the three-dimensional crystal or Cryo-electron microscopy (cryo-EM) structures of the receptor resolved thus far. Their roles in the full-length wild-type receptor activation are not clear.

To solve these problems, scientists led by Drs. WANG Mingwei, Patrick Sexton and Denise Wootten from the Shanghai Institute of Materia Medica of Chinese Academy of Sciences, Fudan University and the Monash Institute of Pharmaceutical Sciences, Australia, spent three years focusing on the N-terminal and TM1 region near the extracellular domain.

By mutating 28 residues, receptor binding affinities and activation efficacies on different signaling pathways (cAMP, pERK1/2 and Ca²⁺) of several peptidic ligands were systematically studied.

They found that different residue groups were able to modulate both affinity and signaling in a varied but overlapping manner, and different ligands bind to the same receptor in different conformation thereby transducing distinct downstream signals.

The results showed that the N-terminal and TM1 region near the extracellular domain of glucagon-like peptide-1 receptor play an important role in controlling peptide-mediated biased agonism, which provides insights into the initiation of receptor activation at molecular level as well as drug design by maximizing the physiological benefit of biased agonism.

This study was published in The Journal of Biological Chemistry. It was supported by National Health and Medical Research Council of Australia, the National Natural Science Foundation of China, Strategic Priority Research Program of Chinese Academy of Sciences and Shanghai Science and Technology Development Fund.

Glucagon-like peptide-1 receptor has been implicated in the treatment of type 2 diabetes and obesity. Therapeutic agents, namely, glucagon-like peptide-1 receptor agonists, currently on the market require different administration frequency and possess variable efficacies, adverse events as well as tolerance, which may be related to the outcome of biased agonism of glucagon-like peptide-1 receptor.

Inactive glucagon-like peptide-1 receptor model and active structure activated by Exendin-P5 in complex with Gs protein (Image by The Journal of Biological Chemistry)