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- PDB-7d68: Cryo-EM structure of the human glucagon-like peptide-2 receptor-G... -

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Basic information

Entry
Database: PDB / ID: 7d68
TitleCryo-EM structure of the human glucagon-like peptide-2 receptor-Gs protein complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Glucagon-like peptide 2 receptor
  • Nanobody-35
  • Pro-glucagon
KeywordsBIOSYNTHETIC PROTEIN / Glucagon-like peptide-2 receptor / Drug target / Class B GPCR
Function / homology
Function and homology information


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 ...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
Similarity search - Function
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. ...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
Similarity search - Domain/homology
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
Similarity search - Component
Biological speciesBos taurus (cattle)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsSun, W. / Chen, L. / Zhou, Q. / Zhao, L. / Zhang, H. / Cong, Z. / Shen, D. / Zhao, F. / Zhou, F. / Cai, X. ...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.
CitationJournal: 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 ...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 ...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
DepositionSep 29, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 16, 2020Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nanobody-35
P: Pro-glucagon
R: Glucagon-like peptide 2 receptor


Theoretical massNumber of molelcules
Total (without water)185,0016
Polymers185,0016
Non-polymers00
Water1267
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14780 Å2
ΔGint-74 kcal/mol
Surface area48110 Å2

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short


Mass: 43897.789 Da / Num. of mol.: 1 / Mutation: G226A, A366S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P04896*PLUS
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 40226.992 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62871
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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Antibody / Protein/peptide / Protein / Non-polymers , 4 types, 10 molecules NPR

#4: Antibody Nanobody-35


Mass: 13711.284 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#5: Protein/peptide Pro-glucagon


Mass: 3769.136 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GCG / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P01275
#6: Protein Glucagon-like peptide 2 receptor


Mass: 75534.836 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLP2R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O95838*PLUS
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Cryo-EM structure of the human glucagon-like peptide-2 receptor-Gs protein complexCOMPLEX#1-#60MULTIPLE SOURCES
2Guanine nucleotide-binding proteinCOMPLEX#1-#31RECOMBINANT
3Nanobody-35COMPLEX#41MULTIPLE SOURCES
4Glucagon-like peptide 2 receptorCOMPLEX#5-#61RECOMBINANT
Molecular weightUnits: MEGADALTONS / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Bos taurus (cattle)9913
23synthetic construct (others)32630
34Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Spodoptera frugiperda (fall armyworm)7108
24Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 64 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 284669 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048746
ELECTRON MICROSCOPYf_angle_d0.6111836
ELECTRON MICROSCOPYf_dihedral_angle_d13.475193
ELECTRON MICROSCOPYf_chiral_restr0.0431318
ELECTRON MICROSCOPYf_plane_restr0.0041506

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