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The structures of receptors involved in blood sugar control

One of the recently reported G-protein-coupled receptor structures: an activated GLP-1 receptor complex with bound GLP-1 in orange. Yan Zhang, Bingfa Sun, et al, Nature

Levels of blood glucose, or blood sugar, are tightly controlled by the body. People with diabetes have difficulty controlling blood glucose levels. High levels of blood glucose can cause serious health problems over time. It can also be dangerous for your blood glucose level to dip too low. Medications such as insulin (which lowers blood glucose) and glucagon (which elevates it in an emergency) can help maintain blood glucose in a safe range. However, glucagon in particular can be difficult to administer.

Blood glucose control depends heavily on proteins called G-protein-coupled receptors (GPCRs). GPCRs span cell membranes to relay signals from the outside in. Once activated by the binding of a substance, GPCRs trigger a cascade of responses inside the cell. These receptors are thus important targets for drug development.

When blood glucose levels drop, such as after an overnight fast, the pancreas releases a hormone called glucagon. Glucagon binds a GPCR on liver and muscle cells called the glucagon receptor, which then stimulates the cells to release glucose into the bloodstream. Another hormone involved in glucose control is called glucagon-like peptide-1 (GLP-1). It works by binding to another GPCR, the GLP-1 receptor, on cells in the pancreas. After a meal, the intestine produces GLP-1, which prompts the pancreas to produce insulin. Insulin, in turn, stimulates cells to take in glucose from the blood.

The glucagon and GLP-1 receptors are both class B GPCRs. The structures of several class A GPCRs have been solved, but class B receptors haven’t been as well studied because of technical challenges. Four international research teams reported the structures of the glucagon and GLP-1 receptors in Nature on June 8, 2017. Two of the teams were supported in part by NIH, including NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of General Medical Sciences (NIGMS), and National Institute on Drug Abuse (NIDA).

The structure of the portion of the glucagon receptor that spans cell membranes was described previously. In one of the new papers, an international team led by Dr. Beili Wu from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, described the structure of the full length human glucagon receptor. The team included NIH-funded groups headed by Drs. Wei Liu at Arizona State University and Vadim Cherezov at the University of Southern California. The researchers crystallized the receptor in an inactive state and used X-ray diffraction with an X-ray free-electron laser to determine its structure.

“The [glucagon receptor] structure provides a clear picture of a full-length class B GPCR at high resolution, and helps us understand how different domains cooperate in modulating the receptor function at the molecular level,” Wu says.

Another NIH-funded team—led by Drs. Brian Kobilka at Stanford University and Georgios Skiniotis at the University of Michigan—described the structure of a GLP-1 receptor. The team used a different technique, cryo-electron microscopy, to examine the structure of the receptor in complex with GLP-1 and its coupled G-protein. The two other accompanying papers detailed the structure of the GLP-1 receptor when bound by small molecules that affect the receptor’s activity.

“It’s hard to overstate the importance of G-protein-coupled receptors,” Skiniotis says. “GPCRs are targeted by about half of all drugs, and getting such structures by cryo-electron microscopy will be crucial for further drug discovery efforts.”

The glucagon and GLP-1 receptors are both important drug targets for type 2 diabetes and obesity. These results may help inform the design of new drugs to regulate blood glucose levels.

—by Harrison Wein, Ph.D.