7D68

Cryo-EM structure of the human glucagon-like peptide-2 receptor-Gs protein complex

Summary for 7D68

• Entry DOI: 10.2210/pdb7d68/pdb
• EMDB information: 30590
• 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, ... (7 entities in total)
• Functional Keywords: glucagon-like peptide-2 receptor, drug target, class b gpcr, biosynthetic protein
• Biological source: Bos taurus; More
• Total number of polymer chains: 6
• Total formula weight: 185001.18

Authors

Sun, W.,Chen, L.,Zhou, Q.,Zhao, L.,Zhang, H.,Cong, Z.,Shen, D.,Zhao, F.,Zhou, F.,Cai, X.,Chen, Y.,Zhou, Y.,Gadgaard, S.,van der Velden, W.J.,Zhao, S.,Jiang, Y.,Rosenkilde, M.M.,Yang, D.,Xu, H.E.,Zhang, Y.,Wang, M. (deposition date: 2020-09-29, release date: 2020-12-16)

Primary citation

Sun, W.,Chen, L.N.,Zhou, Q.,Zhao, L.H.,Yang, D.,Zhang, H.,Cong, Z.,Shen, D.D.,Zhao, F.,Zhou, F.,Cai, X.,Chen, Y.,Zhou, Y.,Gadgaard, S.,van der Velden, W.J.C.,Zhao, S.,Jiang, Y.,Rosenkilde, M.M.,Xu, H.E.,Zhang, Y.,Wang, M.W.
A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor.
Cell Res., 30:1098-1108, 2020

PubMed Abstract: Glucagon-like peptides (GLP-1 and GLP-2) are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors (GLP-1R and GLP-2R) which are important drug targets for metabolic disorders and Crohn's disease, respectively. Despite great progress in GLP-1R structure determination, our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive. Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a G heterotrimer. To accommodate GLP-2 rather than GLP-1, GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices (TMs) 1, 5, 7 and extracellular loop 1 (ECL1). In contrast to GLP-1, the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique orientation. The middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2, and the GLP-2 C-terminus closely attaches to ECL1, which is the most protruded among 9 class B G protein-coupled receptors (GPCRs). Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation, especially the middle region. These results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics.

PubMed: 33239759
DOI: 10.1038/s41422-020-00442-0

Experimental method

ELECTRON MICROSCOPY (3 Å)