A small maneuver space may be the key to effective peptides for the treatment of diabetes

New research shows that peptides (short pieces of protein) used to treat type 2 diabetes may be more effective if they can move flexibly back and forth between different shapes

These findings may help improve the drug design of these diabetes drugs and other therapeutic peptides

More broadly, this discovery refutes the popular belief that the molecular signaling mechanism in the human body is based on having an ideal-and static-partner to activate cell receptors

This peptide is called GLP-1, and it was previously known to be a strict helical shape

Sam Gellman, a professor of chemistry at the University of Wisconsin-Madison, who oversaw the new research, said: “I think most molecular scientists think that the shape of this peptide bound to the receptor is a single ideal shape

On December 22, Gellman and an international team of researchers published their findings in the journal Nature Chemical Biology

Many hormones are peptides, including insulin and GLP-1

Biologists often think of peptides as a key that can enter and unlock the recipient's lock

Drug manufacturers often try to adjust the shape of peptides to make them better drugs

However, when Cary modified glp-1 peptides to better form this helical shape, he found that they were less effective

In order to study this unexpected discovery in depth, Cary designed and created a series of GLP-1 varieties with different shapes for testing

When the research team tested these different shapes, they found a mystery: the helical peptide binds tightly to the receptor, but it is bad at activating it; the kink protein binds weakly, but when they finally dock, they effectively activate Receptor

To solve this problem, the research team proposed a new model of how GLP-1 might work

Gehrman said: "By moving back and forth, but not completely cutting off the receptor, you can continue to send signals, which is more effective as a signal-inducing peptide

This model is supported by data, which shows that glp-1-like peptides bind to receptors in two different shapes

Gehrman said: "The pleasure of seeing the structure of the cryo-electron microscope and recognizing the existence of two states is to see strong evidence that the existence of the second state plays a functional role here

Looking to the future, Gellman said, drugmakers should consider whether the peptides they choose will also benefit from being able to adopt multiple shapes
.

"We usually think of a single idealized structure that we are trying to achieve
.
But I want to conclude from these results: In fact, the most effective way is to ensure that you maintain the flexibility of a particular model
.
" "If you have this Idea, then you are observing the molecule in a different way
.
"

Journal Reference :

1. Brian P.
   Cary, Giuseppe Deganutti, Peishen Zhao, Tin T.
   Truong, Sarah J.
   Piper, Xinyu Liu, Matthew J.
   Belousoff, Radostin Danev, Patrick M.
   Sexton, Denise Wootten, Samuel H.
   Gellman.
   Structural and functional diversity among agonist-bound states of the GLP-1 receptor .
   Nature Chemical Biology , 2021; DOI: 10.
   1038/s41589-021-00945-w