Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor

Figure 1

The activation mechanism of the GLP-1 receptor. Biochemical and structural studies have led to a model of class B1 GPCR activation by peptide hormones referred to as the “two-step” mechanism [82]. (a) In the unliganded state, the GLP-1 receptor (GLP-1R) is in a predominately inactive conformation. The natural ligand GLP-1(7-36)-NH₂ is freely diffusible in solution and likely has substantial intrinsic α-helical structure. (b) An initial binding event between the globular ectodomain at the N-terminal of the GLP-1R and the C-terminal of the GLP-1(7-36)-NH₂ peptide occurs. This “low affinity” interaction acts as a tether or “affinity trap” to localize GLP-1 at the GLP-1R. (c) The weak affinity of the N-terminus of GLP-1(7-36)-NH₂ is then able to productively engage with transmembrane domain and loop residues of the receptor to induce a high affinity interaction and likely a conformational change in the GLP-1R. (d) Coincident with agonist binding, the G-protein bound conformation of the GLP-1R is stabilized. This represents the classic high affinity agonist bound state. (e) The high affinity agonist bound state is transient in an intact system as the GLP-1R stimulates guanine nucleotide exchange on the α-subunit of the G-protein heterotrimer, leading to G-protein dissociation and independent or synergistic activation of effector proteins by liberated Gα·GTP and Gβγ.