Molecular modelling of the GLP-1 receptor: a prototypic class B GPCR

The main aim of this project was to gain an understanding of GLP-1R’s molecular mechanism of action and the key interactions leading to agonist-mediated activation. At the start of this project there were no experimentally determined GLP- 1R structures available, the initial approach was to use experimentally determined structures of other class B GPCRs for GLP-1R homology modelling. Soon different GLP-1R structures became available (Jazayeri et al. 2017; Zhang et al. 2017; Song et al. 2017) providing valuable information. However, none of these structures showed GLP-1R in complex with GLP-1, the endogenous peptide; based on the experimental available structures, GLP-1R -GLP-1 complex models were built and simulated using different methods of molecular dynamics simulations. After defining interactions in the active and inactive state, the second aim was to identify conformational changes leading to activation. Since Class B share structural characteristics and possible an activation mechanism, PTH1 receptor model was built. Simulation of GLP-1R and PTH1 receptor in complex with their respectively ligands show ligands disrupting the TM1-TM2 interface and relying on hydrophobic residues to facilitate the movement into the binding pocket. At the extracellular end, the movement of the ligand into the binding pocket shift TM7 towards TM6, contributing to TM6 rearrangement, in addition interaction between charged residues in the N-terminal and TM6 allowed TM6 flexibility and outward movement while maintaining the stability of the receptor. Interaction between charged residues in the N-terminal and Arg2.60b contribute to the binding and stabilisation of the ligand as translation of conformational changes in TM3-TM2 middle region, where Asn3.43b removes spatial restraints from the core of the receptor. The removal of spatial restrains is seen as TM3-TM2 packing allowing Leu3.47b rotamer change pushing a hydrophobic residue in TM6 resulting in the outward movement stabilised by changes in hydrophobic residues rotamers.