Glucagon receptor structure offers new opportunities for type 2 diabetes drug discovery

January 4, 2018, Chinese Academy of Sciences
The The Crystal Structure of the Full-Length Human Glucagon Receptor (GCGR)crystal structure 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) Credit: Dr. WU Beili

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.

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 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 the understanding of class B GPCR signal transduction. The study was published in Nature.

This study offers some valuable insights into the activation mechanism of GCGR. The most exciting finding 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 in their secondary structures in the peptide-bound GCGR structure compared to the previously determined non-peptide-bound structure. This leads 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 by facilitating conformational movements of the receptor TMD. "It is amazing to observe how the stalk region plays such an important role in regulating , although it only contains 12 amino acids," said SIMM professor Dr. ZHAO Qiang. "This has never been observed in previously solved GPCR structural studies. It significantly deepens the knowledge about class B GPCR signaling mechanisms."

Based on the structure of GCGR-NNC1702 complex, 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 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.

Explore further: Research opens the door to improved drugs for type 2 diabetes

More information: Structure of the glucagon receptor in complex with a glucagon analogue, Nature, nature.com/articles/doi:10.1038/nature25153

Related Stories

Scientists solve structure of complement C5a receptor

January 4, 2018

Scientists at Heptares Therapeutics have published the first high-resolution X-ray crystal structure of the complement C5a receptor (a G protein-coupled receptor, GPCR) binding a small molecule allosteric antagonist.

Unlocking the mystery of pollen tube guidance

January 3, 2018

Fertilization in flowering plants occurs by the delivery of sperm cells to the ovule by the precise growth of pollen tubes from pollen. Pollen tube guidance plays a crucial role in controlling the growth of pollen tubes and ...

Recommended for you

A new polymer raises the bar for lithium-sulfur batteries

January 18, 2018

Lithium-sulfur batteries are promising candidates for replacing common lithium-ion batteries in electric vehicles since they are cheaper, weigh less, and can store nearly double the energy for the same mass. However, lithium-sulfur ...

Looking to the sun to create hydrogen fuel

January 18, 2018

When Lawrence Livermore scientist Tadashi Ogitsu leased a hydrogen fuel-cell car in 2017, he knew that his daily commute would change forever. There are no greenhouse gases that come out of the tailpipe, just a bit of water ...

The early bits of life

January 18, 2018

How can life originate before DNA and genes? One possibility is that there are natural processes that lead to the organisation of simple physical objects such as small microcapsules that undergo rudimentary forms of interaction, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.