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

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Shanghai Institute of Materia Medica, Chinese Academy of Sciences

04 Jan, 2018, 02:24 GMT

- Complex structure of a class B GPCR bound to an analogue of its endogenous ligand ignites new excitement in GPCR research

SHANGHAI, Jan. 4, 2018 /PRNewswire/ -- 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 regulate downstream signal transduction.

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The crystal structures of the full-length human glucagon receptor (GCGR): orange (extracellular domain), blue (transmembrane domain), green (stalk), magenta (the first extracellular loop), red (NNC1702), yellow (NNC0640) and cyan (mAb1). (Image by 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, and thus it is a potential drug target for type 2 diabetes.

Recently, scientists at Shanghai Institute of Materia Medica (SIMM) of Chinese Academy of Sciences, in collaboration with several groups based in China, Denmark, Canada and United States, determined the crystal structure of GCGR in complex with a glucagon analogue 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 the understanding of class B GPCR signal transduction. The study was published in Nature.（The article full text：https://www.nature.com/articles/nature25153）

The most exciting finding of this study is that the linker region connecting the ECD and TMD of the receptor, termed the "stalk," and the first extracellular loop undergo significant conformational changes, leading to a marked change in the relative orientation between the ECD and TMD of the receptor to accommodate peptide binding and initiate receptor activation. Furthermore, the stalk may modulate receptor activity by facilitating conformational movements of the receptor TMD.

The researchers performed a series of functional studies using techniques such as competitive ligand binding, cell signaling, molecular dynamics simulations and double electron-electron resonance spectroscopy. The results support the GCGR structure and confirm the conformational alterations of the receptor in different functional states.

"The newly solved GCGR structure not only helps us understand the signal recognition mechanisms of class B GPCRs, but also provides the most accurate template to date for drug design targeting GCGR, which offers new opportunities in drug discovery for treating type 2 diabetes," said team leader and SIMM professor Dr. WU Beili.

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