5ott

Extracellular domain of GLP-1 receptor in complex with exendin-4 variant Gly2Hcs/Thr5Hcs

spinqualitylabelsall models 5ott, resolution 1.92Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ott is a 2 chain structure with sequence from Heloderma suspectum and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.92Å Ligands: HCS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GLP1R_HUMAN This is a receptor for glucagon-like peptide 1. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. Publication Abstract from PubMed Peptide agonists acting on the glucagon-like peptide 1 receptor (GLP-1R) promote glucose-dependent insulin release and therefore represent important therapeutic agents for type 2 diabetes (T2D). Previous data indicated that an N-terminal type II beta-turn motif might be an important feature for agonists acting on the GLP-1R. In contrast, recent publications reporting the structure of the full-length GLP-1R have shown the N-terminus of receptor-bound agonists in an alpha-helical conformation. To reconcile these conflicting results, we prepared N-terminally constrained analogues of glucagon-like peptide 1 (GLP-1) and exendin-4 and evaluated their receptor affinity and functionality in vitro; we then examined their crystal structures in complex with the extracellular domain of the GLP-1R and used molecular modeling and molecular dynamics simulations for further investigations. We report that the peptides' N-termini in all determined crystal structures adopted a type II beta-turn conformation, but in vitro potency varied several thousand-fold across the series. Potency correlated better with alpha-helicity in our computational model, although we have found that the energy barrier between the two mentioned conformations is low in our most potent analogues and the flexibility of the N-terminus is highlighted by the dynamics simulations. alpha-Helix or beta-Turn? An Investigation into N-Terminally Constrained Analogues of Glucagon-like Peptide 1 (GLP-1) and Exendin-4.,Oddo A, Mortensen S, Thogersen H, De Maria L, Hennen S, McGuire JN, Kofoed J, Linderoth L, Reedtz-Runge S Biochemistry. 2018 Jun 21. doi: 10.1021/acs.biochem.8b00105. PMID:29877701 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glucagon-like peptide receptor 3D structures

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