Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators

Opening a gap for diabetes treatment

14 December 2017

A clearer understanding of the structure of a receptor involved in the breakdown of glucose could lead to the development of new drugs for type II diabetes.

After eating, the hormone glucagon-like peptide-1 (GLP-1) combines with the receptor GLP-1R on pancreatic cells, leading to insulin secretion and a reduction in blood glucose. A better understanding of the receptor’s structure could instruct the design of drugs that target specific areas to enhance its effectiveness in promoting insulin secretion.

Researchers at China’s Shanghai Tech University and colleagues crystallized GLP-1R and examined its structure using X-rays. They also induced mutations in the receptor to see how silencing specific genes affected the receptor’s function. They found that certain compounds combine with GLP-1R, locking out a protein, called G-protein, from ‘switching on’ the receptor. Another type of compound, on the other hand, combines with GLP-1R in a way that not only allows the G-protein to interact with the receptor, but opens up a gap for GLP-1 and its analogues to bind to it. This clearer understanding of GLP-1R’s structure and function could help model the development of new diabetes drugs.

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References

1. Nature 546, 312–315 (2017). doi: 10.1038/nature22378