Peptides may be more effective in treating diabetes, according to a recent study, if they were more flexible and could switch back and forth between different forms.
The study was published in the “Nature Chemical Biology Journal”.
The results could help improve drug designs for these diabetes drugs and possibly other therapeutic peptides.
More generally, the discovery countered the common wisdom that this molecular signaling machinery in the body is based on having an ideal – and static – partner to activate cell receptors. The machinery of life could be more dynamic than previously thought.
ALSO READ: How Children With Type 1 Diabetes Can Stay Safe Amid Omicron Wave
The peptide, known as GLP-1, was previously known to take on a rigidly helical corkscrew shape. Compared to a peptide locked in this helical shape, a peptide designed to form a sudden fold near its end activated its cellular target better, which in turn promoted the release of insulin from the pancreas. It is likely that in the body GLP-1 is able to switch between these two forms, thereby maximizing its potency.
âI think most molecular scientists have a picture of this receptor-bound peptide as having a single ideal form,â said Sam Gellman, professor of chemistry at the University of Wisconsin-Madison who oversaw the new research.
“And what we’re saying is that this view of an ideal interaction between these two units is probably too simplistic. To be effective, this peptide has to remain mobile in some way,” Gellman added.
The work was led by Brian Cary when he was a doctoral student in Gellman’s lab.
Many hormones are peptides, including insulin and GLP-1. These peptides provided key information to cells that affected metabolism, for example by controlling blood sugar. Peptides transmit this information by binding to and activating specialized receptor proteins outside of a cell.
Biologists often think of the peptide as a key that fits into the receptor lock and transforms it. Just like with keys, the right shape is essential for a peptide to function properly.
Drug makers often try to adjust the shape of a peptide to make it a better drug. As GLP-1 takes on a corkscrew shape, the hypothesis was that forcing the peptide to be more helical might make GLP-1 more apt to activate its target in the body.
Yet when Cary designed GLP-1-like peptides to better form this corkscrew shape, he found they were less potent.
To dig into this unexpected discovery, Cary designed and created a series of different shaped GLP-1 varieties to test. Using amino acids not normally found in naturally occurring peptides, Cary was able to produce two types of shapes. One category was helical along its entire length, while the other was bent at a severe angle near one end.
When the research team tested these different forms, they discovered a conundrum: the helical peptides bound tightly to the receptor, but were terrible at activating it; elbow proteins bound weakly, but effectively activated the receptor when they finally docked.
To solve this puzzle, the team proposed a new operating model for GLP-1. In this model, GLP-1 binds to its target and activates it in the form of a helix – the key properly formed to fit the lock. Then GLP-1 is able to change to a new shape with a crease towards the end. The fold helps reset the cellular target of GLP-1, preparing it to send out a new signal. The peptide could then revert to a helix to fully dock again and activate the target again.
âBy going back and forth, but never completely getting out of the receptor, you continue to signal and be more effective as a signal inducing peptide,â Gellman said.
Only a peptide capable of rocking back and forth can accomplish this feat.
This model was supported by data showing a GLP-1-like peptide bound to its receptor in two different forms. This molecular-level imaging of the shape of different proteins, known as Cryo-EM, has helped scientists see how biological machines fit together to function.
âThe thrill of seeing this Cryo-EM structure and recognizing that there are two states was to see strong evidence that there is a second state that plays a functional role here,â said Gellman.
Going forward, Gellman said drugmakers should consider whether their peptides of choice might also benefit from the ability to adopt multiple forms.
“We usually think of a single idealized structure that we are trying to achieve. But I would conclude from these results that in fact the most effective way is to make sure you maintain particular modes of flexibility,” he said. declared.
“If you have that idea in mind, then you look at the molecule in different ways,” he added.
This story was posted from an agency feed with no text editing.