内化
受体
兴奋剂
胰高血糖素样肽1受体
肠促胰岛素
内分泌学
生长抑素
内科学
化学
刺激
胰高血糖素样肽-1
激素
生物
细胞生物学
生物化学
2型糖尿病
医学
糖尿病
作者
Wijnand J C van der Velden,Florent Xavier Smit,C. Christiansen,Thor C. Møller,Gertrud Malene Hjortø,Olav Larsen,Sine P. Schiellerup,Hans Bräuner‐Osborne,Jens J. Holst,Bolette Hartmann,Thomas M. Frimurer,Mette M. Rosenkilde
出处
期刊:ACS pharmacology & translational science
[American Chemical Society]
日期:2021-01-19
卷期号:4 (1): 296-313
被引量:24
标识
DOI:10.1021/acsptsci.0c00193
摘要
Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification in the incretin hormone glucagon-like peptide (GLP-1) that alters the signaling capabilities of the GLP-1 receptor (GLP-1R) by making it G protein biased over internalization but was originally designed to confer DPP-4 resistance and thereby prolong the half-life of GLP-1. Despite similar binding affinity, cAMP production, and calcium mobilization, substitution of a single amino acid (Ala8 to Val8) in the N-terminus of GLP-1(7-36)NH2 (GLP-1 Val8) severely impaired its ability to internalize GLP-1R compared to endogenous GLP-1. In-depth binding kinetics analyses revealed shorter residence time for GLP-1 Val8 as well as a slower observed association rate. Molecular dynamics (MD) displayed weaker and less interactions of GLP-1 Val8 with GLP-1R, as well as distinct conformational changes in the receptor compared to GLP-1. In vitro validation of the MD, by receptor alanine substitutions, confirmed stronger impairments of GLP-1 Val8-mediated signaling compared to GLP-1. In a perfused rat pancreas, acute stimulation with GLP-1 Val8 resulted in a lower insulin and somatostatin secretion compared to GLP-1. Our study illustrates that profound differences in molecular pharmacological properties, which are essential for the therapeutic targeting of the GLP-1 system, can be induced by subtle changes in the N-terminus of GLP-1. This information could facilitate the development of optimized GLP-1R agonists.
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