2mj9

Designed Exendin-4 analogues

spinqualitylabelsall models 2mj9 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2mj9 is a 1 chain structure with sequence from Heloderma suspectum. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 10 models Ligands: DAL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function EXE4_HELSU Venom protein that mimics the incretin hormone glucagon-like peptide 1 (GLP-1). It stimulates insulin synthesis and secretion, protects against beta-cell apoptosis in response to different insults, and promotes beta-cell proliferation. It also promotes satiety, reduces food intake, reduces fat deposition, reduces body weight and inhibits gastric emptying. Interacts with GLP-1 receptor (GLP1R). Induces hypotension that is mediated by relaxation of cardiac smooth muscle. Publication Abstract from PubMed Exendin-4 (Ex4) is a potent glucagon-like peptide-1 receptor agonist, a drug regulating the plasma glucose level of patients suffering from type 2 diabetes. The molecule's poor solubility and its readiness to form aggregates increase the likelihood of unwanted side effects. Therefore, we designed Ex4 analogues with improved structural characteristics and better water solubility. Rational design was started from the parent 20-amino acid, well-folded Trp cage (TC) miniprotein and involved the step-by-step N-terminal elongation of the TC head, resulting in the 39-amino acid Ex4 analogue, E19. Helical propensity coupled to tertiary structure compactness was monitored and quantitatively analyzed by electronic circular dichroism and nuclear magnetic resonance (NMR) spectroscopy for the 14 peptides of different lengths. Both 15N relaxation- and diffusion-ordered NMR measurements were established to investigate the inherent mobility and self-association propensity of Ex4 and E19. Our designed E19 molecule has the same tertiary structure as Ex4 but is more helical than Ex4 under all studied conditions; it is less prone to oligomerization and has preserved biological activity. These conditions make E19 a perfect lead compound for further drug discovery. We believe that this structural study improves our understanding of the relationship between local molecular features and global physicochemical properties such as water solubility and could help in the development of more potent Ex4 analogues with improved pharmacokinetic properties. Rational Design of alpha-Helix-Stabilized Exendin-4 Analogues.,Rovo P, Farkas V, Straner P, Szabo M, Jermendy A, Hegyi O, Toth GK, Perczel A Biochemistry. 2014 May 28. PMID:24828921 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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