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- PDB-6lmk: Cryo-EM structure of the human glucagon receptor in complex with Gs -

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Basic information

Entry
Database: PDB / ID: 6lmk
TitleCryo-EM structure of the human glucagon receptor in complex with Gs
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Glucagon
  • Glucagon receptor
  • Nb35
KeywordsSIGNALING PROTEIN / glucagon receptor / GPCR / Gs protein
Function / homology
Function and homology information


glucagon receptor binding / regulation of glycogen metabolic process / glucagon receptor activity / : / negative regulation of execution phase of apoptosis / feeding behavior / response to starvation / positive regulation of calcium ion import / peptide hormone binding / PKA activation in glucagon signalling ...glucagon receptor binding / regulation of glycogen metabolic process / glucagon receptor activity / : / negative regulation of execution phase of apoptosis / feeding behavior / response to starvation / positive regulation of calcium ion import / peptide hormone binding / PKA activation in glucagon signalling / developmental growth / Synthesis, secretion, and deacylation of Ghrelin / hair follicle placode formation / D1 dopamine receptor binding / intracellular transport / positive regulation of insulin secretion involved in cellular response to glucose stimulus / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / response to nutrient / cellular response to glucagon stimulus / positive regulation of gluconeogenesis / regulation of insulin secretion / guanyl-nucleotide exchange factor activity / adenylate cyclase activator activity / cellular response to starvation / trans-Golgi network membrane / gluconeogenesis / response to activity / generation of precursor metabolites and energy / negative regulation of inflammatory response to antigenic stimulus / hormone activity / bone development / platelet aggregation / regulation of blood pressure / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / cognition / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / sensory perception of smell / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / glucose homeostasis / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / positive regulation of cold-induced thermogenesis / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity / GTPase binding / Ca2+ pathway / fibroblast proliferation / secretory granule lumen / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / cell population proliferation / positive regulation of ERK1 and ERK2 cascade / receptor ligand activity
Similarity search - Function
GPCR, family 2, glucagon receptor / Glucagon / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / GPCR, family 2, glucagon-like peptide-1/glucagon receptor / G-protein coupled receptors family 2 signature 1. ...GPCR, family 2, glucagon receptor / Glucagon / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / GPCR, family 2, glucagon-like peptide-1/glucagon receptor / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / 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. / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / G-protein alpha subunit, group S / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / Few Secondary Structures / Irregular / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / WD domain, G-beta repeat / 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. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Up-down Bundle / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Pro-glucagon / Glucagon receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsQiao, A. / Han, S. / Tai, L. / Sun, F. / Zhao, Q. / Wu, B.
Funding support China, 8items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2018YFA0507000 China
Ministry of Science and Technology (MoST, China)2017YFA0504703 China
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)81525024 China
National Science Foundation (NSF, China)31830020 China
Chinese Academy of SciencesQYZDB-SSW-SMC024 China
Chinese Academy of SciencesQYZDB-SSW-SMC054 China
Ministry of Science and Technology (MoST, China)2018ZX09711002 China
CitationJournal: Science / Year: 2020
Title: Structural basis of G and G recognition by the human glucagon receptor.
Authors: Anna Qiao / Shuo Han / Xinmei Li / Zhixin Li / Peishen Zhao / Antao Dai / Rulve Chang / Linhua Tai / Qiuxiang Tan / Xiaojing Chu / Limin Ma / Thor Seneca Thorsen / Steffen Reedtz-Runge / ...Authors: Anna Qiao / Shuo Han / Xinmei Li / Zhixin Li / Peishen Zhao / Antao Dai / Rulve Chang / Linhua Tai / Qiuxiang Tan / Xiaojing Chu / Limin Ma / Thor Seneca Thorsen / Steffen Reedtz-Runge / Dehua Yang / Ming-Wei Wang / Patrick M Sexton / Denise Wootten / Fei Sun / Qiang Zhao / Beili Wu /
Abstract: Class B G protein-coupled receptors, an important class of therapeutic targets, signal mainly through the G class of heterotrimeric G proteins, although they do display some promiscuity in G protein ...Class B G protein-coupled receptors, an important class of therapeutic targets, signal mainly through the G class of heterotrimeric G proteins, although they do display some promiscuity in G protein binding. Using cryo-electron microscopy, we determined the structures of the human glucagon receptor (GCGR) bound to glucagon and distinct classes of heterotrimeric G proteins, G or G These two structures adopt a similar open binding cavity to accommodate G and G The G binding selectivity of GCGR is explained by a larger interaction interface, but there are specific interactions that affect G more than G binding. Conformational differences in the receptor intracellular loops were found to be key selectivity determinants. These distinctions in transducer engagement were supported by mutagenesis and functional studies.
History
DepositionDec 26, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 1, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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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
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nb35
R: Glucagon receptor
E: Glucagon


Theoretical massNumber of molelcules
Total (without water)159,3156
Polymers159,3156
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area16530 Å2
ΔGint-105 kcal/mol
Surface area50580 Å2

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Components

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

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


Mass: 45683.434 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: unidentified baculovirus / References: UniProt: P63092
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38744.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: unidentified baculovirus / References: UniProt: P62873
#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.) Homo sapiens (human) / Gene: GNG2 / Production host: unidentified baculovirus / References: UniProt: P59768

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Antibody / Protein / Protein/peptide , 3 types, 3 molecules NRE

#4: Antibody Nb35


Mass: 15140.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#5: Protein Glucagon receptor / GL-R


Mass: 48398.109 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GCGR / Production host: unidentified baculovirus / References: UniProt: P47871
#6: Protein/peptide Glucagon


Mass: 3486.781 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01275

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Details

Has protein modificationY

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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

ComponentName: Complex of glucagon receptor bound to glucagon, Gs protein and nanobody
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: unidentified baculovirus
Buffer solutionpH: 7.5
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: 1.875 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareVersion: 9.03 / Category: image acquisition
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 169878 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 88.54 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00879447
ELECTRON MICROSCOPYf_angle_d0.950512810
ELECTRON MICROSCOPYf_chiral_restr0.05831419
ELECTRON MICROSCOPYf_plane_restr0.00671641
ELECTRON MICROSCOPYf_dihedral_angle_d17.75763366

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