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H. sapiens Glucose-dependent Insulinotropic Polypeptide

spinqualitylabelsall models GIP Structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Introduction Glucose-dependent insulinotropic polypeptide(GIP) is a gastric inhibitory polypeptide, composed of 42 amino acids. It is categorized as an incretin, which is a gut-based hormone that is secreted upon the ingestion of food. It is found in K cells in the upper small intestines of humans. History The idea of incretin, and subsequently GIP, began in 1902 after the discovery of secretin by Bayliss and Starling. Inspired by their discovery, Moore et al. hypothesized that there must be some kind of gut hormone that regulates the endocrine pancreas. His experiments showed that gut extracts in patients with diabetes have reduced amounts of sugars in their urine as a result of endocrine stimulation. In 1929, a French scientist named La Barre was able to purify incretin (INtestine seCREtion INsulin) from gut extracts. The idea of incretin slowly lost attention until the 1960s when radioimmunoassay became available to measure incretin levels. GIP and GLP-1 (glucagon-like peptide-1) were the two gut based hormones that were proven to act as incretins. GIP was found to be located in the K cells of the upper small intestines in humans. At first, it was titled a gastric inhibitory polypeptide because of its ability to inhibit gastric acid secretion after being isolating from porcine intestines. Later, they discovered that when GIP was administered in healthy volunteers, it stimulated insulin secretion by acting directly on pancreatic islets. As a result of these discoveries, they renamed it glucose-dependent insulinotropic polypeptide, becoming the first known incretin. Structure Overview G-proteins GIP is a G-coupled receptor. It is a 7 helical transmembrane domain with the ligand in dark blue and the helices in light blue. It contains alpha, beta, and gamma subunits located in the intracellular domain. The G alpha subunit makes interactions with the beta and gamma subunits that when bound to ATP, activates the G alpha protein and is released by the other subunits to bind to target, i.e. adenylyl cycle in order to activate the process of insulin secretion. Function This is a default text for your page Mandy Bechman/Sandbox 1. Click above on edit this page to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia or to the article describing Jmol to the rescue. Function Mechanism of GIP activation and deactivation. The mechanism of GIP begins with the ingestion of food. This stimulates GIP to bind to its receptor. Once bound, the activated G alpha protein moves laterally in the membrane in order to activate its target, adenylyl cyclase. Once adenylyl cyclase is activated, it catalyzes the formation of cyclic AMP (cAMP). This molecule activates Protein Kinase A (PKA), which signals the secretin of insulin. After a few minutes of active signaling, this hormone is recognized and inactivated by a peptidase called DPP-4 (dipeptidyl peptidase-4) by cleaving the first two amino acids. Importance Tirzepatide One of the most promising treatments to GIP malfunction is Tirzepatide, also known as Mounharo, created by Eli Lily. It is an antidiabetic as well as weight loss drug. The structure of Tirzepatide functions as an incretin receptor agonist to GIP by activating GIP's receptor and producing insulin. Sequence comparison of the first 28 residues of GIP and Tirzepatide. Relevance In GIP, the residue 2 is an alanine but in Tirzepatide, the residue changes to AIB Structural highlights Structure of alanine converted to AIB. This is a sample scene created with SAT to color by Group, and another to make a transparent representation of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

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Mandy Bechman