7LLY

Oxyntomodulin-bound Glucagon-Like Peptide-1 (GLP-1) Receptor in complex with Gs protein

Summary for 7LLY

• Entry DOI: 10.2210/pdb7lly/pdb
• EMDB information: 23436
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: glucagon-like peptide-1 (glp-1) receptor, oxyntomodulin, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 164535.36

Authors

Wootten, D.,Sexton, P.M.,Belousoff, M.J.,Danev, R.,Zhang, X.,Khoshouei, M.,Venugopal, H. (deposition date: 2021-02-04, release date: 2022-01-12, Last modification date: 2025-05-21)

Primary citation

Deganutti, G.,Liang, Y.L.,Zhang, X.,Khoshouei, M.,Clydesdale, L.,Belousoff, M.J.,Venugopal, H.,Truong, T.T.,Glukhova, A.,Keller, A.N.,Gregory, K.J.,Leach, K.,Christopoulos, A.,Danev, R.,Reynolds, C.A.,Zhao, P.,Sexton, P.M.,Wootten, D.
Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation.
Nat Commun, 13:92-92, 2022

PubMed Abstract: The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists.

PubMed: 35013280
DOI: 10.1038/s41467-021-27760-0

Experimental method

ELECTRON MICROSCOPY (3.3 Å)