Flexible peptides can be more effective in diabetes treatments, says study

Peptides could be more effective to treat diabetes if they were more flexible and could move back and forth between different shapes according to a recent studyThe study has been published in the Nature Chemical Biology JournalThe findings could help improve drug design for these diabetes drugs and possibly other therapeutic peptidesMore broadly the discovery countered common wisdom that that molecular signalling machinery in the body is based on having one ideal and static partner to activate cellular receptors Lifes machinery might be more dynamic than previously thoughtThe peptide known as GLP1 had previously been known to adopt a rigidly helical corkscrew shape Compared to a peptide locked into this helical shape a peptide engineered to form a sudden kink near its end better activated its cellular target which promoted insulin release from the pancreas Its likely that in the body GLP1 is able to switch back and forth between these two forms maximising its potencyI think most molecular scientists have an image of this peptide bound to the receptor as having a single ideal shape said Sam Gellman a professor of chemistry at the University of WisconsinMadison who supervised the new researchAnd what were saying is that this vision of an ideal interaction between these two units is probably too simplistic That in order to be effective that peptide needs to remain mobile in certain ways Gellman addedThe work was led by Brian Cary when he was a doctoral student in Gellmans labMany hormones are peptides including insulin and GLP1 These peptides provided key information to cells that affected metabolism such as by controlling blood sugar Peptides pass on this information by binding to and activating specialized receptor proteins on the outside of a cellBiologists often imagine the peptide as a key that fits into and turns the receptors lock Just like for keys the right shape is critical for a peptide to work properlyDrugmakers often try to adjust a peptides shape to make it a better drug Because GLP1 adopts a corkscrew shape the assumption was that forcing the peptide to be more helical might make GLP1 better able to activate its target in the bodyYet when Cary engineered GLP1like peptides to better form this corkscrew shape he discovered that they were less potentTo dig into this unexpected finding Cary designed and created a series of differently shaped GLP1 varieties to test Using amino acids not normally found in natural peptides Cary was able to produce two types of shapes One category was helical throughout its length while the other one bent at a severe angle close to one endWhen the research team tested these different shapes they uncovered a puzzle helical peptides bound strongly to the receptor but were terrible at activating it kinked proteins bound weakly but effectively activated the receptor when they finally docked inTo solve this puzzle the team came up with a new model of how GLP1 might work In this model GLP1 binds to and activates its target as a helix the correctly shaped key to fit in the lock Then GLP1 is able to switch to a new shape with a kink near the end The kink helps reset GLP1s cellular target preparing it to send a new signal The peptide could then switch back to a helix to fully dock again and activate the target once moreBy going back and forth but never completely popping off the receptor you get to keep signalling and be more effective as a signalinducing peptide said GellmanOnly a peptide that is able to switch back and forth can accomplish this featThis model was supported by data showing a GLP1like peptide bound to its receptor in two different shapes This molecularlevel imaging of the shape of different proteins known as CryoEM helped scientists see how biological machinery fits together to functionThe pleasure of seeing that CryoEM structure and recognizing that there are two states was seeing strong evidence that there is a second state that plays a functional role here said GellmanGoing forward Gellman said that drug makers should consider whether their peptides of choice may similarly benefit from being able to adopt multiple shapesWe generally think of a single idealized structure that we are trying to obtain But I would conclude from these results that actually the way to be most effective is to ensure you maintain particular modes of flexibility he saidIf you have that idea in mind then youre looking at the molecule in different ways he addedThis story has been sourced from a third party syndicated feed agencies Midday accepts no responsibility or liability for its dependability trustworthiness reliability and data of the text Midday managementmiddaycom reserves the sole right to alter delete or remove without notice the content in its absolute discretion for any reason whatsoever