6VCB

Cryo-EM structure of the Glucagon-like peptide-1 receptor in complex with G protein, GLP-1 peptide and a positive allosteric modulator

Summary for 6VCB

• Entry DOI: 10.2210/pdb6vcb/pdb
• EMDB information: 21147
• Descriptor: Glucagon-like peptide 1 receptor, Glucagon-like peptide 1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (7 entities in total)
• Functional Keywords: g protein-coupled receptor, membrane protein, family b gpcr, diabetes, allosteric modulator, signaling protein-membrane protein complex, signaling protein/membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 163147.10

Authors

Sun, B.,Feng, D.,Bueno, A.,Kobilka, B.,Sloop, K. (deposition date: 2019-12-20, release date: 2020-07-22, Last modification date: 2024-10-23)

Primary citation

Bueno, A.B.,Sun, B.,Willard, F.S.,Feng, D.,Ho, J.D.,Wainscott, D.B.,Showalter, A.D.,Vieth, M.,Chen, Q.,Stutsman, C.,Chau, B.,Ficorilli, J.,Agejas, F.J.,Cumming, G.R.,Jimenez, A.,Rojo, I.,Kobilka, T.S.,Kobilka, B.K.,Sloop, K.W.
Structural insights into probe-dependent positive allosterism of the GLP-1 receptor.
Nat.Chem.Biol., 16:1105-1110, 2020

PubMed Abstract: Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a 'molecular glue'. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of GLP-1(7-36). The compound enhances insulin secretion in a glucose-, ligand- and GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric G. The modulator binds high in the helical bundle at an interface between TM1 and TM2, allowing access to the peptide ligand. Pharmacological characterization showed strong probe dependence of LSN3160440 for GLP-1(9-36) versus oxyntomodulin that is driven by a single residue. Our findings expand protein-protein modulation drug discovery to uncompetitive, active state stabilizers for peptide hormone receptors.

PubMed: 32690941
DOI: 10.1038/s41589-020-0589-7

Experimental method

ELECTRON MICROSCOPY (3.3 Å)