DPP-4 and GLP-1

After meals, the stomach releases a chemical messenger called Incretins, hormones that travel to the pancrease and signal the release of insulin. The body has a built in regulation system used to control the amount of insulin released. Floating throughout the blood stream, and on the surface of many cells, are enyzamatic proteins that degrade Incretins before they can reach the pancrease. This protein interaction shuts off the insulin signaling processes gradually. This protein interaction is also the target for a slew of new pharmaceutical therapies designed to target the interaction of incretins like GLP-1 and DDP-4.

GLP-1 degradation by DPP-4

GLP-1 3D protein model

After printing out protein data-sets (2RGU and1DOR) a couple of things become immediately clear about how these proteins interact. When GLP-1 is deactivated, DPP-4 will clip from it two amino acids. These amino acids are denoted by their atomic colors on our protein model seen above. In addition, the DDP-4 data-set reveals the binding site of the enzymatic protein located deep inside an internal chamber. This site is easily found since the protein was crystallized while inhibited by a pharmacetuical compound known as linagliptin.

DPP-4 Interior Binding Pocket

DPP-4 Interior bound by inhibitor (center grey)

 

 

 

 

 

Snuggled inside the protein, DPP-4 inhibitors like Linagliptin prevent incretin degradation blocking access to the protein’s binding site. It’s not clear exactly how this inhibits DPP-4′s degradation of GLP-1, but its possible that DPP-4 engulfs the protein in order to trigger the degradation event.

GLP-1’s Functional Conformational Changes

Just as interesting as discovering the “monster” like nature that DPP-4 will gobble up incretins by clipping off their tails, after sifting through the data-set for GLP-1, we can visualize something more about the protein’s potential mobility and the impact DPP-4 inactivation has on GLP-1′s ability to reach the pancrease.

Inside of protein data-set 1D0R are a series of theoretically stable conformations of the GLP-1 protein. These are amino acid configurations that achieve a stable secondary protein structure. This information reveals some exciting insights into potential mobility of incretins like GLP-1. Seen in this video are selected samples of that protein data, morphing from position to position over time. When seen this way, it becomes clear that the most structurally dynamic portion of the protein is also the portion of the protein degraded by DPP-4. We know incretins travel some amount of distance in the body, going from one organ to another, could it be that incretins propel themselves through a propeller like propulsion system?

We think this idea is fascinating, and while we can not definitively say for certain if GLP-1′s mobility is due to this, once again an important physiological process can be easily explained with 3D protein models made from x-ray crystallography data-sets.

Casey Steffen M.Sci.