A mechanism for agonist activation of the glucagon-like peptide-1 (GLP-1) receptor through modelling & molecular dynamics

• Published in: Biochemical and biophysical research communications 2018-03, Vol.498 (2), p.359-365
• Main Authors: Gómez Santiago, Carla, Paci, Emanuele, Donnelly, Dan
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Diabetes; DRUGS; GLP-1; GLUCAGON; GPCR; GTP-ASES; Incretin; METABOLIC DISEASES; Molecular dynamics; RECEPTORS
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.01.110

The receptor for glucagon-like peptide 1 (GLP-1R) is a validated drug target for the treatment of type 2 diabetes and obesity. Recently the first three structures of GLP-1R were published – an X-ray structure of the apo transmembrane domain in the inactive conformation; an X-ray structure of the full-length receptor bound to a truncated peptide agonist; and a cryo-EM structure of the full-length receptor bound with GLP-1 and coupled to the G protein Gs. Since the inactive structure was incomplete, and the two active-state structures shared significant differences, we utilised all available knowledge to build hybrid models of the full length active and inactive state receptors. The two models were simulated using molecular dynamics and the output trajectories analysed and compared to reveal insights into the mechanism for agonist-mediated receptor activation. His-7, Glu-9 and Asp-15 of GLP-1 act together to destabilise transmembrane helix 6 and extracellular loop 3 in order to generate an active conformation of GLP-1R. [Display omitted] •Two structures for active-state GLP-1R have been published in 2017.•There are aspects of these structures which are incompatible with each other.•We built a hybrid model using both structures and subjected it to molecular dynamics.•We propose a mechanism for agonist-mediated receptor activation.