A sugar high in structural biology – Nature.com
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Most people know about mouth-to-mouth resuscitation and chest compressions, even if they have never had to put them into practice. Some could probably attempt the Heimlich manoeuvre. But how many have heard of glucagon rescue?
To a person with diabetes who has dangerously low blood sugar, a shot of the hormone glucagon delivered by someone else is their best chance of survival. Many carry a life-saving glucagon rescue kit. But it’s difficult to use in a hurry. A powder must be mixed into solution, shaken and then delivered with a hypodermic syringe. Even people who are practised struggle. To those who are unfamiliar, the lengthy instructions can be enough to stop them from trying. If a pupil falls into a hypoglycaemic coma, teachers in some US schools have it written into their contracts that they are to call the emergency services instead.
So research that could lead to a better way to address hypoglycaemia and other complications of diabetes is an urgent pursuit. This week, Nature publishes four papers that describe such work. At first glance, the research might seem far removed from the medical front line. It’s hardcore structural biology: solved crystal and cryo-electron microscopy (cryo-EM) structures of G-protein-coupled receptors. But the insights could improve glucagon rescue, and lead to other treatments for diabetes and obesity.
In the body, glucagon triggers the conversion of stored glycogen to glucose — the opposite effect to insulin. Stable synthetic insulin is routine in medicine, but glucagon poses more of a problem. Solutions of it go off, hence the tricky rescue kits. Research that could make glucagon solutions stable and rescue kits simpler would have a life-saving impact. How to achieve that? The hormone increases glucose levels by triggering a biochemical sequence that is heavily dependent on a signalling protein. A related signalling protein activates insulin to mop up excess glucose. Type 2 diabetes causes problems because it disrupts this balance. The full structure of these signalling proteins was unknown — until now.
The two proteins are glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR). Their activation and deactivation have opposing roles in glucose homeostasis and insulin release, and so help to regulate metabolism and appetite. They are activated by peptides, which could be adapted as potential drugs. Design of peptide or small-molecule drugs requires data on how and where the molecules bind — information now revealed in the structures. Indeed, in one of the studies, researchers designed a new peptide molecule that activates GLP-1R in mice (A. Jazayeri et al. Nature 546, 254–258; 2017).
Another describes the use of cryo-EM to solve the GLP-1R activated structure in complex with its G protein signalling partner (Y. Zhang et al. Nature 546, 248–253; 2017). It shows how the receptor grabs and secures the peptide, then twists to pass on the signal. Finally, two others report the structures of GLP-1R and GCGR in their inactive forms — both deactivated by small molecules that bind to a different site from the natural hormone (G. Song et al. Nature 546, 312–315 (2017) and H. Zhang et al. Nature 546, 259–264 (2017)). Because small-molecule drugs are easier to design than peptide-hormone mimics, these structures suggest new therapeutic opportunities for regulating glucose homeostasis.
The need is great: in trials, even parents trained to use the kits on their children took an average of 2.5 minutes to mix and deliver glucagon. And many injected nothing but fresh air. They need a helping hand. Structural biology is trying to provide just that.