9g20

Trp-cage fortified Tc5b-Exenatide chimera (Ex4-Tc5bER) at 310KTrp-cage fortified Tc5b-Exenatide chimera (Ex4-Tc5bER) at 310K

Structural highlights 9g20 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 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 Exenatide (Ex4), a GLP-1 incretin mimetic polypeptide, is an effective therapeutic agent against diabetes and obesity. We highlight the indirect role of Ex4's structure-stabilizing Trp-cage (Tc) motif in governing GLP-1 receptor (GLP-1R) signal transduction. We use various Ex4 derivatives to explore how Tc compactness influences thermal stability, aggregation, enhancement of insulin secretion, and GLP-1R binding. We found that Ex4 variants decorated with fortified Tc motifs exhibit increased resistance to unfolding and aggregation but show an inverse relationship between the bioactivity and stability. Molecular dynamics simulations coupled with a rigid-body segmentation protocol to analyze dynamic interconnectedness revealed that the constrained Tc motifs remain intact within the receptor-ligand complexes but interfere with one of the major stabilizing contacts and recognition loci on the extracellular side of GLP-1R, dislodging the N-terminal activating region of the hormone mimetics, and restrict the free movement of TM6, the main signal transduction device of GLP-1R. Influence of Trp-Cage on the Function and Stability of GLP-1R Agonist Exenatide Derivatives.,Horvath D, Straner P, Taricska N, Fazekas Z, Menyhard DK, Perczel A J Med Chem. 2024 Sep 10. doi: 10.1021/acs.jmedchem.4c01553. PMID:39254428 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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