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- PDB-7f9z: GHRP-6-bound ghrelin receptor in complex with Gq -

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Basic information

Entry
Database: PDB / ID: 7f9z
TitleGHRP-6-bound ghrelin receptor in complex with Gq
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • 3-PYRIDIN-4-YL-2,4-DIHYDRO-INDENO[1,2-.C.]PYRAZOLE
  • Engineered G-alpha-q
  • Nb35
  • human ghrelin receptorGrowth hormone secretagogue receptor
  • scFv16
KeywordsMEMBRANE PROTEIN / ghrelin / GPCR / Gq / GHRP-6
Function / homology
Function and homology information


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 activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor ...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 activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / 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 / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
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 ...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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
polypeptide(D) / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
Lama glama (llama)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWang, Y. / Zhuang, Y. / Xu, P. / Xu, H.E. / Jiang, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31770796 China
CitationJournal: Nat Commun / Year: 2021
Title: Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor.
Authors: Yue Wang / Shimeng Guo / Youwen Zhuang / Ying Yun / Peiyu Xu / Xinheng He / Jia Guo / Wanchao Yin / H Eric Xu / Xin Xie / Yi Jiang /
Abstract: Ghrelin, also called "the hunger hormone", is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature ...Ghrelin, also called "the hunger hormone", is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of G-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.
History
DepositionJul 5, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 18, 2021Provider: repository / Type: Initial release
Revision 2.0Mar 16, 2022Group: Advisory / Atomic model ...Advisory / Atomic model / Author supporting evidence / Data collection / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / citation / citation_author / em_imaging / em_software / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / pdbx_contact_author / pdbx_entity_instance_feature / pdbx_entity_src_syn / pdbx_poly_seq_scheme / pdbx_struct_assembly_prop / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / pdbx_validate_close_contact / pdbx_validate_torsion / struct_conf / struct_conn / struct_mon_prot_cis / struct_ref / struct_ref_seq / struct_sheet_range
Item: _atom_site_anisotrop.id / _atom_site_anisotrop.pdbx_auth_comp_id ..._atom_site_anisotrop.id / _atom_site_anisotrop.pdbx_auth_comp_id / _atom_site_anisotrop.pdbx_label_asym_id / _atom_site_anisotrop.pdbx_label_comp_id / _citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _em_imaging.nominal_defocus_max / _em_imaging.nominal_defocus_min / _em_software.category / _em_software.fitting_id / _em_software.imaging_id / _entity.formula_weight / _entity.pdbx_description / _entity.src_method / _entity_name_com.entity_id / _entity_poly.nstd_monomer / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_poly.pdbx_strand_id / _entity_poly.type / _entity_poly_seq.entity_id / _entity_poly_seq.mon_id / _entity_poly_seq.num / _entity_src_gen.entity_id / _entity_src_gen.gene_src_common_name / _pdbx_entity_instance_feature.auth_comp_id / _pdbx_entity_instance_feature.comp_id / _pdbx_entity_src_syn.entity_id / _pdbx_poly_seq_scheme.asym_id / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.auth_seq_num / _pdbx_poly_seq_scheme.entity_id / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.ndb_seq_num / _pdbx_poly_seq_scheme.pdb_ins_code / _pdbx_poly_seq_scheme.pdb_mon_id / _pdbx_poly_seq_scheme.pdb_seq_num / _pdbx_poly_seq_scheme.pdb_strand_id / _pdbx_poly_seq_scheme.seq_id / _pdbx_struct_sheet_hbond.range_1_label_asym_id / _pdbx_struct_sheet_hbond.range_2_label_asym_id / _pdbx_unobs_or_zero_occ_residues.label_asym_id / _pdbx_validate_torsion.auth_asym_id / _pdbx_validate_torsion.auth_comp_id / _pdbx_validate_torsion.auth_seq_id / _pdbx_validate_torsion.phi / _pdbx_validate_torsion.psi / _struct_conf.beg_label_asym_id / _struct_conf.end_label_asym_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_label_asym_id / _struct_mon_prot_cis.auth_asym_id / _struct_mon_prot_cis.auth_comp_id / _struct_mon_prot_cis.auth_seq_id / _struct_mon_prot_cis.label_asym_id / _struct_mon_prot_cis.label_comp_id / _struct_mon_prot_cis.label_seq_id / _struct_mon_prot_cis.pdbx_auth_asym_id_2 / _struct_mon_prot_cis.pdbx_auth_comp_id_2 / _struct_mon_prot_cis.pdbx_auth_seq_id_2 / _struct_mon_prot_cis.pdbx_label_asym_id_2 / _struct_mon_prot_cis.pdbx_label_comp_id_2 / _struct_mon_prot_cis.pdbx_label_seq_id_2 / _struct_mon_prot_cis.pdbx_omega_angle / _struct_ref.db_code / _struct_ref.db_name / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.pdbx_strand_id / _struct_ref_seq.seq_align_end / _struct_sheet_range.beg_label_asym_id / _struct_sheet_range.end_label_asym_id
Description: Sequence discrepancy / Details: The A308 residue of the R chain is corrected to S. / Provider: author / Type: Coordinate replacement

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Structure visualization

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  • Deposited structure unit
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Assembly

Deposited unit
A: Engineered G-alpha-q
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: 3-PYRIDIN-4-YL-2,4-DIHYDRO-INDENO[1,2-.C.]PYRAZOLE
E: scFv16
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nb35
R: human ghrelin receptor


Theoretical massNumber of molelcules
Total (without water)213,1797
Polymers213,1797
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules AR

#1: Protein Engineered G-alpha-q


Mass: 41855.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#7: Protein human ghrelin receptor / Growth hormone secretagogue receptor


Mass: 74282.609 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG

#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.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#5: 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Polypeptide(D) , 1 types, 1 molecules C

#3: Polypeptide(D) 3-PYRIDIN-4-YL-2,4-DIHYDRO-INDENO[1,2-.C.]PYRAZOLE


Mass: 873.014 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Antibody , 2 types, 2 molecules EN

#4: Antibody scFv16


Mass: 32736.527 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Antibody Nb35


Mass: 15343.019 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)

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Details

Has ligand of interestY

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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: GHRP-6-bound ghrelin receptor in complex with Gq / Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
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: OTHER
Electron lensMode: OTHER / Nominal defocus max: 3000 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 262892 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00210197
ELECTRON MICROSCOPYf_angle_d0.48613817
ELECTRON MICROSCOPYf_dihedral_angle_d21.6611399
ELECTRON MICROSCOPYf_chiral_restr0.041553
ELECTRON MICROSCOPYf_plane_restr0.0041753

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