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- PDB-7epf: Crystal structure of mGlu2 bound to NAM597 -

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Entry
Database: PDB / ID: 7epf
TitleCrystal structure of mGlu2 bound to NAM597
ComponentsMetabotropic glutamate receptor 2
KeywordsMEMBRANE PROTEIN / GPCR
Function / homologyFLAVIN MONONUCLEOTIDE / Chem-J9U
Function and homology information
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsDu, J. / Wang, D. / Lin, S. / Han, S. / Wu, B. / Zhao, Q.
Funding support China, 4items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)81525024 China
National Science Foundation (NSF, China)31830020 China
National Science Foundation (NSF, China)81720108031 China
CitationJournal: Nature / Year: 2021
Title: Structures of human mGlu2 and mGlu7 homo- and heterodimers.
Authors: Juan Du / Dejian Wang / Hongcheng Fan / Chanjuan Xu / Linhua Tai / Shuling Lin / Shuo Han / Qiuxiang Tan / Xinwei Wang / Tuo Xu / Hui Zhang / Xiaojing Chu / Cuiying Yi / Peng Liu / Xiaomei ...Authors: Juan Du / Dejian Wang / Hongcheng Fan / Chanjuan Xu / Linhua Tai / Shuling Lin / Shuo Han / Qiuxiang Tan / Xinwei Wang / Tuo Xu / Hui Zhang / Xiaojing Chu / Cuiying Yi / Peng Liu / Xiaomei Wang / Yu Zhou / Jean-Philippe Pin / Philippe Rondard / Hong Liu / Jianfeng Liu / Fei Sun / Beili Wu / Qiang Zhao /
Abstract: The metabotropic glutamate receptors (mGlus) are involved in the modulation of synaptic transmission and neuronal excitability in the central nervous system. These receptors probably exist as both ...The metabotropic glutamate receptors (mGlus) are involved in the modulation of synaptic transmission and neuronal excitability in the central nervous system. These receptors probably exist as both homo- and heterodimers that have unique pharmacological and functional properties. Here we report four cryo-electron microscopy structures of the human mGlu subtypes mGlu2 and mGlu7, including inactive mGlu2 and mGlu7 homodimers; mGlu2 homodimer bound to an agonist and a positive allosteric modulator; and inactive mGlu2-mGlu7 heterodimer. We observed a subtype-dependent dimerization mode for these mGlus, as a unique dimer interface that is mediated by helix IV (and that is important for limiting receptor activity) exists only in the inactive mGlu2 structure. The structures provide molecular details of the inter- and intra-subunit conformational changes that are required for receptor activation, which distinguish class C G-protein-coupled receptors from those in classes A and B. Furthermore, our structure and functional studies of the mGlu2-mGlu7 heterodimer suggest that the mGlu7 subunit has a dominant role in controlling dimeric association and G-protein activation in the heterodimer. These insights into mGlu homo- and heterodimers highlight the complex landscape of mGlu dimerization and activation.
History
DepositionApr 26, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 23, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation_author.name
Revision 1.2Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3Oct 23, 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: Metabotropic glutamate receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,3503
Polymers48,4971
Non-polymers8542
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area800 Å2
ΔGint-7 kcal/mol
Surface area17130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.501, 86.440, 99.815
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21221
Space group name HallP22ab(y,z,x)
Symmetry operation#1: x,y,z
#2: x+1/2,-y,-z+1/2
#3: -x,y,-z
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Metabotropic glutamate receptor 2 / mGlu2


Mass: 48496.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Baculovirus expression vector pFastBac1-HM
#2: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P
#3: Chemical ChemComp-J9U / (8~{R})-4-[2,4-bis(fluoranyl)phenyl]-8-methyl-7-[(2-methylpyrazol-3-yl)methyl]-6,8-dihydro-5~{H}-1,7-naphthyridine-2-carboxamide


Mass: 397.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H21F2N5O / Feature type: SUBJECT OF INVESTIGATION
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: 2.6 Å3/Da / Density % sol: 52.73 %
Crystal growTemperature: 293.15 K / Method: lipidic cubic phase
Details: 100 mM MES, pH 6.0~6.5, 50~200 mM NaCl, 50~150 mM MgCl2, 20%~35% (v/v) PEG 400

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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: Oct 15, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→50 Å / Num. obs: 14332 / % possible obs: 98.5 % / Redundancy: 8.2 % / Biso Wilson estimate: 85.03 Å2 / Rmerge(I) obs: 0.169 / Net I/σ(I): 25.8
Reflection shellResolution: 2.7→2.8 Å / Rmerge(I) obs: 0.91 / Num. unique obs: 1349

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Processing

Software
NameVersionClassification
PHENIX1.19.2refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4OR2, 1I1O

4or2

1i1o


Resolution: 2.7→43.59 Å / Cross valid method: FREE R-VALUE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2863 674 -
Rwork0.2578 --
obs-14121 100 %
Displacement parametersBiso mean: 96.26 Å2
Refinement stepCycle: LAST / Resolution: 2.7→43.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2833 0 60 0 2893
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01282959
X-RAY DIFFRACTIONf_angle_d1.73684047
X-RAY DIFFRACTIONf_chiral_restr0.1028482
X-RAY DIFFRACTIONf_plane_restr0.01520
X-RAY DIFFRACTIONf_dihedral_angle_d18.615993
LS refinement shellResolution: 2.7→2.91 Å
RfactorNum. reflection% reflection
Rfree0.3887 --
Rwork0.3359 --
obs-2642 94 %

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