5VEX

Structure of the human GLP-1 receptor complex with NNC0640

Summary for 5VEX

• Entry DOI: 10.2210/pdb5vex/pdb
• Related: 5VEW
• Descriptor: Glucagon-like peptide 1 receptor, Endolysin chimera, 4-{[(4-cyclohexylphenyl){[3-(methylsulfonyl)phenyl]carbamoyl}amino]methyl}-N-(1H-tetrazol-5-yl)benzamide (2 entities in total)
• Functional Keywords: gpcr, class b, 7tm domain, treatment of type 2 diabetes, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane; Multi-pass membrane protein: P43220
• Total number of polymer chains: 2
• Total formula weight: 106321.83

Authors

Song, G.,Yang, D.,Wang, Y.,Graaf, C.D.,Zhou, Q.,Jiang, S.,Liu, K.,Cai, X.,Dai, A.,Lin, G.,Liu, D.,Wu, F.,Wu, Y.,Zhao, S.,Ye, L.,Han, G.W.,Lau, J.,Wu, B.,Hanson, M.A.,Liu, Z.-J.,Wang, M.-W.,Stevens, R.C. (deposition date: 2017-04-05, release date: 2017-05-17, Last modification date: 2024-10-30)

Primary citation

Song, G.,Yang, D.,Wang, Y.,de Graaf, C.,Zhou, Q.,Jiang, S.,Liu, K.,Cai, X.,Dai, A.,Lin, G.,Liu, D.,Wu, F.,Wu, Y.,Zhao, S.,Ye, L.,Han, G.W.,Lau, J.,Wu, B.,Hanson, M.A.,Liu, Z.J.,Wang, M.W.,Stevens, R.C.
Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators.
Nature, 546:312-315, 2017

PubMed Abstract: The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 Å resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs. Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.

PubMed: 28514449
DOI: 10.1038/nature22378

Experimental method

X-RAY DIFFRACTION (3 Å)