Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor–Gs complex

Abstract

The class B glucagon-like peptide-1 (GLP-1) G protein-coupled receptor is a major target for the treatment of type 2 diabetes and obesity. Endogenous and mimetic GLP-1 peptides exhibit biased agonism-a difference in functional selectivity-that may provide improved therapeutic outcomes. Here we describe the structure of the human GLP-1 receptor in complex with the G protein-biased peptide exendin-P5 and a Gα heterotrimer, determined at a global resolution of 3.3 Å. At the extracellular surface, the organization of extracellular loop 3 and proximal transmembrane segments differs between our exendin-P5-bound structure and previous GLP-1-bound GLP-1 receptor structure. At the intracellular face, there was a six-degree difference in the angle of the Gαs-α5 helix engagement between structures, which was propagated across the G protein heterotrimer. In addition, the structures differed in the rate and extent of conformational reorganization of the Gα protein. Our structure provides insights into the molecular basis of biased agonism.

Preassociation between the 5‐HT 7 serotonin receptor and G protein G s : molecular determinants and association with low potency activation of adenylyl cyclase

“…To elucidate how the identified domains in TM5 and helix 8 interacted with G s , computational homology modeling was performed with the WT and chimeric 5-HT 7 receptors. Due to a lack of crystal structures consisting of an inactive preassembled receptor-G protein complex, we based our structure on the active receptor-G s complex of the b 2adrenergic receptor because this receptor displayed the closest phylogenetic relationship with 5-HT 7 of all receptors crystalized in a complex with G s (3)(4)(5)29). Our model (Fig.…”

Structural biology of G protein‐coupled receptor signaling complexes

“…The first two cryo‐EM GPCR complex structures were determined for glucagon‐like peptide 1 receptor (GLP1R) and calcitonin receptor (CTR), both in complex with the stimulatory Gs protein . Entering 2018, a cryo‐EM structure of rhodopsin in complex with Gi, a homologue of the G protein transducin, and three other structures, μ‐opioid receptor (μOR) –Gi complex, adenosine A 1 receptor (A 1 R)‐Gi complex, and serotonin 5‐HT 1b R in complex with Go, have been reported . Most recently, a crystal structure of bovine rhodopsin in complex with a mini‐Go that includes the Ras domain of Gαo subunit, was published …”

“…10,11 Entering 2018, a cryo-EM structure of rhodopsin in complex with Gi, a homologue of the G protein transducin, and three other structures, μ-opioid receptor (μOR) -Gi complex, adenosine A 1 receptor (A 1 R)-Gi complex, and serotonin 5-HT 1b R in complex with Go, have been reported. [12][13][14][15] Most recently, a crystal structure of bovine rhodopsin in complex with a mini-Go that includes the Ras domain of Gαo subunit, was published. 16 Rhodopsin is a prototypical GPCR that has served as a model system for structural and biological studies of the whole superfamily of GPCRs.…”

Receptor selectivity between the G proteins Gα 12 and Gα 13 is defined by a single leucine‐to‐isoleucine variation

“…It has long been appreciated that the C-terminal a5 helix of G protein a subunits engages with the active state receptor and that this is a crucial step toward triggering guanine nucleotide exchange on the G protein a subunit to initiate steps that result in regulation of signal transduction cascades (6,7). Although still limited in number (8)(9)(10)(11), structural complexes of an active state GPCR and a G protein have provided validation of such models that were developed over many years. Such a role of the extreme C-terminal region of the G protein a subunit in engaging the agonistoccupied receptor had been predicted.…”