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- PDB-7f83: Crystal Structure of a receptor in Complex with inverse agonist -

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Basic information

Entry
Database: PDB / ID: 7f83
TitleCrystal Structure of a receptor in Complex with inverse agonist
ComponentsGrowth hormone secretagogue receptor type 1,Soluble cytochrome b562
KeywordsSIGNALING PROTEIN / GPCR / Ghrelin / Inverse agonist
Function / homology
Function and homology information


growth hormone secretagogue receptor activity / regulation of hindgut contraction / regulation of growth hormone secretion / growth hormone-releasing hormone receptor activity / positive regulation of small intestinal transit / negative regulation of locomotion involved in locomotory behavior / regulation of gastric motility / regulation of transmission of nerve impulse / ghrelin secretion / response to follicle-stimulating hormone ...growth hormone secretagogue receptor activity / regulation of hindgut contraction / regulation of growth hormone secretion / growth hormone-releasing hormone receptor activity / positive regulation of small intestinal transit / negative regulation of locomotion involved in locomotory behavior / regulation of gastric motility / regulation of transmission of nerve impulse / ghrelin secretion / response to follicle-stimulating hormone / positive regulation of appetite / growth hormone secretion / negative regulation of norepinephrine secretion / positive regulation of eating behavior / positive regulation of small intestine smooth muscle contraction / negative regulation of macrophage apoptotic process / adult feeding behavior / negative regulation of appetite / actin polymerization or depolymerization / positive regulation of multicellular organism growth / cellular response to thyroid hormone stimulus / response to growth hormone / positive regulation of insulin-like growth factor receptor signaling pathway / regulation of postsynapse organization / positive regulation of vascular endothelial cell proliferation / response to food / negative regulation of interleukin-1 beta production / positive regulation of fatty acid metabolic process / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / cellular response to insulin-like growth factor stimulus / response to L-glutamate / regulation of synapse assembly / positive regulation of sprouting angiogenesis / response to dexamethasone / negative regulation of interleukin-6 production / peptide hormone binding / decidualization / negative regulation of tumor necrosis factor production / postsynaptic modulation of chemical synaptic transmission / negative regulation of insulin secretion / response to hormone / hormone-mediated signaling pathway / insulin-like growth factor receptor signaling pathway / Peptide ligand-binding receptors / synaptic membrane / electron transport chain / G protein-coupled receptor activity / Schaffer collateral - CA1 synapse / negative regulation of inflammatory response / cellular response to insulin stimulus / response to estradiol / cellular response to lipopolysaccharide / spermatogenesis / G alpha (q) signalling events / periplasmic space / learning or memory / electron transfer activity / postsynapse / neuron projection / G protein-coupled receptor signaling pathway / iron ion binding / membrane raft / heme binding / glutamatergic synapse / cell surface / identical protein binding / plasma membrane
Similarity search - Function
Growth hormone secretagogue receptor/motilin receptor / Cytochrome c/b562 / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Four Helix Bundle (Hemerythrin (Met), subunit A) / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. ...Growth hormone secretagogue receptor/motilin receptor / Cytochrome c/b562 / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Four Helix Bundle (Hemerythrin (Met), subunit A) / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-1KQ / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / Soluble cytochrome b562 / Growth hormone secretagogue receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.94 Å
AuthorsXu, Z. / Shao, Z.
CitationJournal: Nat Commun / Year: 2022
Title: Molecular mechanism of agonism and inverse agonism in ghrelin receptor.
Authors: Jiao Qin / Ye Cai / Zheng Xu / Qianqian Ming / Su-Yu Ji / Chao Wu / Huibing Zhang / Chunyou Mao / Dan-Dan Shen / Kunio Hirata / Yanbin Ma / Wei Yan / Yan Zhang / Zhenhua Shao /
Abstract: Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are ...Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are considered useful therapeutic agents, but the molecular mechanism of such ligands remains insufficiently understood. Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. Our structures reveal a distinct binding mode of the inverse agonist PF-05190457 in the ghrelin receptor, different from the binding mode of agonists and neutral antagonists. Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors.
History
DepositionJul 1, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 19, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 26, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._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
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Growth hormone secretagogue receptor type 1,Soluble cytochrome b562
B: Growth hormone secretagogue receptor type 1,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)97,53110
Polymers94,3662
Non-polymers3,1658
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2680 Å2
ΔGint-22 kcal/mol
Surface area40470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)84.710, 58.680, 119.240
Angle α, β, γ (deg.)90.00, 90.60, 90.00
Int Tables number4
Space group name H-MP1211
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Growth hormone secretagogue receptor type 1,Soluble cytochrome b562 / GHS-R / GH-releasing peptide receptor / GHRP / Ghrelin receptor / Cytochrome b-562


Mass: 47183.223 Da / Num. of mol.: 2 / Mutation: T130K,N188Q,M1012W,H1107I,R1111L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: GHSR, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92847, UniProt: P0ABE7
#2: Chemical
ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C21H40O4
#3: Chemical ChemComp-1KQ / 2-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-1-[2-[(1R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone


Mass: 512.669 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H32N6OS
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.09 Å3/Da / Density % sol: 60.15 %
Crystal growTemperature: 293.15 K / Method: lipidic cubic phase / pH: 7
Details: 100mM HEPES, pH 7.0, 25%-36% PEG300, 80mM - 150mM NH4F

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 7, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.94→39.78 Å / Num. obs: 25315 / % possible obs: 100 % / Redundancy: 24.53 % / Biso Wilson estimate: 81.38 Å2 / Rmerge(I) obs: 0.664 / Net I/σ(I): 10.37
Reflection shellResolution: 2.94→3.12 Å / Redundancy: 23.68 % / Rmerge(I) obs: 5.083 / Mean I/σ(I) obs: 1.31 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.19.2-4158refinement
XDSdata reduction
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6KO5

6ko5


Resolution: 2.94→39.78 Å / SU ML: 0.415 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.565
Stereochemistry target values: GEOSTD + MONOMER LIBRARY + CDL V1.2
RfactorNum. reflection% reflection
Rfree0.265 1239 4.9 %
Rwork0.227 --
obs0.229 25289 100 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 74.27 Å2
Refinement stepCycle: LAST / Resolution: 2.94→39.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6025 0 202 0 6227
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0066367
X-RAY DIFFRACTIONf_angle_d1.0318633
X-RAY DIFFRACTIONf_dihedral_angle_d26.395942
X-RAY DIFFRACTIONf_chiral_restr0.0521004
X-RAY DIFFRACTIONf_plane_restr0.0091053
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.94-3.060.33081180.27292628X-RAY DIFFRACTION100
3.06-3.20.33181590.262619X-RAY DIFFRACTION100
3.2-3.370.3061230.24292672X-RAY DIFFRACTION100
3.37-3.580.27071490.23882634X-RAY DIFFRACTION100
3.58-3.850.25031280.2142691X-RAY DIFFRACTION100
3.85-4.240.25411580.20842664X-RAY DIFFRACTION100
4.24-4.850.23891470.21182649X-RAY DIFFRACTION100
4.85-6.110.30431460.24652690X-RAY DIFFRACTION100
6.11-39.780.22241110.21482803X-RAY DIFFRACTION100

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