EMDB-30590: Cryo-EM structure of the human glucagon-like peptide-2 receptor-G...

Basic information

• Entry: Database: EMDB / ID: EMD-30590
• Title: Cryo-EM structure of the human glucagon-like peptide-2 receptor-Gs protein complex

Sample

• Complex: Cryo-EM structure of the human glucagon-like peptide-2 receptor-Gs protein complex
  • Complex: Guanine nucleotide-binding protein
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Complex: Nanobody-35
    • Protein or peptide: Nanobody-35
  • Complex: Glucagon-like peptide 2 receptor
    • Protein or peptide: Pro-glucagon
    • Protein or peptide: Glucagon-like peptide 2 receptor
• Ligand: water

Function / homology

Function:

glucagon receptor binding / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / glucagon receptor activity / sensory perception of chemical stimulus / Activation of the phototransduction cascade / negative regulation of execution phase of apoptosis / G protein-coupled peptide receptor activity / feeding behavior / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of calcium ion import / cellular response to glucagon stimulus / response to starvation / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peptide hormone binding / regulation of insulin secretion / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / D1 dopamine receptor binding / Synthesis, secretion, and deacylation of Ghrelin / beta-2 adrenergic receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of gluconeogenesis / negative regulation of inflammatory response to antigenic stimulus / protein kinase A signaling / adenylate cyclase activator activity / positive regulation of peptidyl-threonine phosphorylation / response to activity / gluconeogenesis / G protein-coupled receptor activity / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / Glucagon signaling in metabolic regulation / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / positive regulation of peptidyl-serine phosphorylation / glucose homeostasis / G alpha (s) signalling events / G alpha (q) signalling events / secretory granule lumen / membrane => GO:0016020 / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / signaling receptor binding / GTPase activity / positive regulation of cell population proliferation / GTP binding / negative regulation of apoptotic process / extracellular space / extracellular region / identical protein binding / membrane / metal ion binding / plasma membrane / cytoplasm

Domain/homology:

GPCR family 2, glucagon-like peptide 2 receptor / Glucagon / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / GPCR family 2, extracellular hormone receptor domain superfamily / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / G-protein alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase

Component:

Glucagon-like peptide 2 receptor / Pro-glucagon / 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

• Biological species: Bos taurus (cattle) / synthetic construct (others) / Homo sapiens (human)
• Method: single particle reconstruction / cryo EM / Resolution: 3.0 Å
• 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 WJ / Zhao S / Jiang Y / Rosenkilde MM / Yang D / Xu HE / Zhang Y / Wang M
• Citation: Journal: Cell Res / Year: 2020; Title: A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor.; Authors: Wen Sun / Li-Nan Chen / Qingtong Zhou / Li-Hua Zhao / Dehua Yang / Huibing Zhang / Zhaotong Cong / Dan-Dan Shen / Fenghui Zhao / Fulai Zhou / Xiaoqing Cai / Yan Chen / Yan Zhou / Sarina Gadgaard / Wijnand J C van der Velden / Suwen Zhao / Yi Jiang / Mette M Rosenkilde / H Eric Xu / Yan Zhang / Ming-Wei Wang / ; 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.

History

Deposition	Sep 29, 2020	-
Header (metadata) release	Dec 16, 2020	-
Map release	Dec 16, 2020	-
Update	Dec 16, 2020	-
Current status	Dec 16, 2020	Processing site: PDBj / Status: Released