Glucagon Receptor Structure Offers New Opportunities for Type 2 Diabetes Drug Discovery

Class B G protein-coupled receptors (GPCRs) exert essential action in hormonal homeostasis and are important therapeutic targets for a variety of diseases including metabolic disorders such as type 2 diabetes. These receptors consist of an extracellular domain (ECD) and a transmembrane domain (TMD), both of which are required to interact with their cognate peptide ligands and to regulate downstream signal transduction. Due to difficulties in high-quality protein preparation, determination of the structure of full-length class B GPCRs remains a challenge, thus limiting the understanding of molecular mechanisms of receptor action.

Image Source: Dr. WU Beili (PRNewsfoto/Shanghai Institute of Materia M)

Activation of the human glucagon receptor (GCGR) by its endogenous ligand glucagon triggers the release of glucose from the liver during fasting, making it a potential drug target for type 2 diabetes. Last year, a group of scientists at the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences determined the crystal structure of the full-length GCGR bound to a negative allosteric modulator NNC0640 and an inhibitory antibody mAb1, thus providing for the first time a clear picture of a full-length class B GPCR at high resolution.

Recently, scientists at SIMM determined the crystal structure of GCGR in complex with a glucagon analogue and partial agonist NNC1702. This structure reveals, for the first time, the molecular details of a class B GPCR binding to its peptide ligand at high resolution and unexpectedly discloses the structural complexity that governs receptor activation, thereby greatly expanding our understanding of class B GPCR signal transduction. The study was published in Nature. (Shanghai Institute of Materia Medica, Chinese Academy of Sciences)