2nav | pdb_00002nav

NMR solution structure of Ex-4[1-16]/pl14a

spinqualitylabelsall models 2nav, 20 NMR models Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2nav is a 1 chain structure. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. NonStd Res: NH2 Related: 2naw Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Glucagon-like peptide-1 (GLP-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N-terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP-1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide alpha-conotoxin pl14a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fraction helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C-terminal helical segment (residues 22-27) directing the binding of Phe22 into a hydrophobic pocket on the GLP-1R. Truncated glucagon-like peptide-1 and exendin-4 alpha-conotoxin pl14a peptide chimeras maintain potency, alpha-helicity and reveal interactions vital for cAMP signaling in vitro.,Swedberg JE, Schroeder CI, Mitchell J, Fairlie DP, Edmonds DJ, Griffith DA, Ruggeri RB, Derksen DR, Loria PM, Price DA, Liras S, Craik DJ J Biol Chem. 2016 May 10. pii: jbc.M116.724542. PMID:27226591 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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