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

Journal: Nature

Published: 2017-05-17

DOI: 10.1038/nature22378

Affiliations: 14

Authors: 22

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Research Highlight

Opening a gap for diabetes treatment

© ballyscanlon/DigitalVision/Getty

© ballyscanlon/DigitalVision/Getty

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.

Supported content

  1. Nature 546, 312–315 (2017). doi: 10.1038/nature22378
Institutions FC
iHuman Institute, ShanghaiTech, China 0.32
School of Life Science and Technology (SLST), ShanghaiTech, China 0.16
School of Pharmacy, Fudan University, China 0.10
CAS Key Laboratory of Receptor Research (CASKLRR), SIMM CAS, China 0.09
National Center for Drug Screening, China 0.08
University of Chinese Academy of Sciences (UCAS), China 0.05
Novo Nordisk A/S, Denmark 0.05
GPCR Consortium, United States of America (USA) 0.05
Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Netherlands 0.02
Division of Medicinal Chemistry, VU University Amsterdam, Netherlands 0.02
USC Bridge Institute, United States of America (USA) 0.02
USC Department of Chemistry, United States of America (USA) 0.02
Institute of Molecular and Clinical Medicine, KMU, China 0.02

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