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- PDB-6n4x: Metabotropic Glutamate Receptor 5 Apo Form Ligand Binding Domain -

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Basic information

Entry
Database: PDB / ID: 6n4x
TitleMetabotropic Glutamate Receptor 5 Apo Form Ligand Binding Domain
ComponentsMetabotropic glutamate receptor 5
KeywordsMEMBRANE PROTEIN / Cell Surface Receptor
Function / homology
Function and homology information


A2A adenosine receptor binding / regulation of translational elongation / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / positive regulation of long-term neuronal synaptic plasticity / : / desensitization of G protein-coupled receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway ...A2A adenosine receptor binding / regulation of translational elongation / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / positive regulation of long-term neuronal synaptic plasticity / : / desensitization of G protein-coupled receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / astrocyte projection / Class C/3 (Metabotropic glutamate/pheromone receptors) / protein kinase C-activating G protein-coupled receptor signaling pathway / glutamate receptor activity / Neurexins and neuroligins / protein tyrosine kinase activator activity / : / positive regulation of protein tyrosine kinase activity / regulation of synaptic transmission, glutamatergic / protein tyrosine kinase binding / dendritic shaft / locomotory behavior / learning / G protein-coupled receptor activity / postsynaptic density membrane / synapse organization / regulation of protein phosphorylation / Schaffer collateral - CA1 synapse / cognition / cellular response to amyloid-beta / regulation of translation / chemical synaptic transmission / G alpha (q) signalling events / dendritic spine / positive regulation of MAPK cascade / learning or memory / glutamatergic synapse / regulation of DNA-templated transcription / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
GPCR, family 3, metabotropic glutamate receptor 5 / Metabotropic glutamate receptor, Homer-binding domain / Homer-binding domain of metabotropic glutamate receptor / GluR_Homer-bdg / GPCR, family 3, metabotropic glutamate receptor / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR ...GPCR, family 3, metabotropic glutamate receptor 5 / Metabotropic glutamate receptor, Homer-binding domain / Homer-binding domain of metabotropic glutamate receptor / GluR_Homer-bdg / GPCR, family 3, metabotropic glutamate receptor / G-protein coupled receptors family 3 signature 1. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain / GPCR, family 3, nine cysteines domain superfamily / Nine Cysteines Domain of family 3 GPCR / GPCR, family 3, conserved site / G-protein coupled receptors family 3 signature 3. / GPCR, family 3 / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / G-protein coupled receptors family 3 profile. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Metabotropic glutamate receptor 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 4 Å
AuthorsKoehl, A. / Hu, H. / Feng, D. / Sun, B. / Weis, W.I. / Skiniotis, G.S. / Mathiesen, J.M. / Kobilka, B.K.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS092695 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS028471 United States
CitationJournal: Nature / Year: 2019
Title: Structural insights into the activation of metabotropic glutamate receptors.
Authors: Antoine Koehl / Hongli Hu / Dan Feng / Bingfa Sun / Yan Zhang / Michael J Robertson / Matthew Chu / Tong Sun Kobilka / Toon Laeremans / Jan Steyaert / Jeffrey Tarrasch / Somnath Dutta / ...Authors: Antoine Koehl / Hongli Hu / Dan Feng / Bingfa Sun / Yan Zhang / Michael J Robertson / Matthew Chu / Tong Sun Kobilka / Toon Laeremans / Jan Steyaert / Jeffrey Tarrasch / Somnath Dutta / Rasmus Fonseca / William I Weis / Jesper M Mathiesen / Georgios Skiniotis / Brian K Kobilka /
Abstract: Metabotropic glutamate receptors are family C G-protein-coupled receptors. They form obligate dimers and possess extracellular ligand-binding Venus flytrap domains, which are linked by cysteine-rich ...Metabotropic glutamate receptors are family C G-protein-coupled receptors. They form obligate dimers and possess extracellular ligand-binding Venus flytrap domains, which are linked by cysteine-rich domains to their 7-transmembrane domains. Spectroscopic studies show that signalling is a dynamic process, in which large-scale conformational changes underlie the transmission of signals from the extracellular Venus flytraps to the G protein-coupling domains-the 7-transmembrane domains-in the membrane. Here, using a combination of X-ray crystallography, cryo-electron microscopy and signalling studies, we present a structural framework for the activation mechanism of metabotropic glutamate receptor subtype 5. Our results show that agonist binding at the Venus flytraps leads to a compaction of the intersubunit dimer interface, thereby bringing the cysteine-rich domains into close proximity. Interactions between the cysteine-rich domains and the second extracellular loops of the receptor enable the rigid-body repositioning of the 7-transmembrane domains, which come into contact with each other to initiate signalling.
History
DepositionNov 20, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 23, 2019Provider: repository / Type: Initial release
Revision 1.1Feb 6, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Feb 20, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Metabotropic glutamate receptor 5
B: Metabotropic glutamate receptor 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)198,3659
Polymers197,0142
Non-polymers1,3527
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Runs as a dimer, native gel electrophoresis, Runs as a dimer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1580 Å2
ΔGint1 kcal/mol
Surface area45000 Å2
Unit cell
Length a, b, c (Å)119.084, 174.100, 180.902
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number17
Space group name H-MP2221
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 24 through 118 or resid 140...
21(chain B and ((resid 24 through 25 and (name N...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11GLUGLUILEILE(chain A and (resid 24 through 118 or resid 140...AA24 - 11830 - 124
12LYSLYSPHEPHE(chain A and (resid 24 through 118 or resid 140...AA140 - 231146 - 237
13LYSLYSLYSLYS(chain A and (resid 24 through 118 or resid 140...AA232238
14GLUGLUCYSCYS(chain A and (resid 24 through 118 or resid 140...AA24 - 54930 - 555
15GLUGLUCYSCYS(chain A and (resid 24 through 118 or resid 140...AA24 - 54930 - 555
16GLUGLUCYSCYS(chain A and (resid 24 through 118 or resid 140...AA24 - 54930 - 555
17GLUGLUCYSCYS(chain A and (resid 24 through 118 or resid 140...AA24 - 54930 - 555
21GLUGLUARGARG(chain B and ((resid 24 through 25 and (name N...BB24 - 2530 - 31
22GLUGLUPROPRO(chain B and ((resid 24 through 25 and (name N...BB24 - 53630 - 542
23GLUGLUPROPRO(chain B and ((resid 24 through 25 and (name N...BB24 - 53630 - 542

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Components

#1: Protein Metabotropic glutamate receptor 5 / / mGluR5


Mass: 98506.844 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRM5, GPRC1E, MGLUR5 / Plasmid: PVL1392 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41594
#2: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: Mg

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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: 4.76 Å3/Da / Density % sol: 74.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 15% PEG 3350, 0.2M Na Cacodylate pH 6.5

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Data collection

DiffractionMean temperature: 78 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 7, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 4→49.57 Å / Num. obs: 30328 / % possible obs: 94 % / Redundancy: 6.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.14 / Rpim(I) all: 0.054 / Rrim(I) all: 0.151 / Net I/σ(I): 11.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
4-4.226.71.67143900.470.6671.80894.2
12.65-49.576.40.0549970.9980.020.05789.1

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Processing

Software
NameVersionClassification
PHENIX1.14_3211refinement
Aimless0.1.26data scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6N4Y

6n4y


Resolution: 4→49.569 Å / SU ML: 0.51 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 29.45
RfactorNum. reflection% reflectionSelection details
Rfree0.2821 1538 5.08 %Random Selection
Rwork0.2699 ---
obs0.2706 30266 93.15 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 295.12 Å2 / Biso mean: 184.4453 Å2 / Biso min: 105.84 Å2
Refinement stepCycle: final / Resolution: 4→49.569 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7651 0 85 0 7736
Biso mean--218.27 --
Num. residues----993
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A4468X-RAY DIFFRACTION6.379TORSIONAL
12B4468X-RAY DIFFRACTION6.379TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 11

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
4-4.12910.36251470.33332567271493
4.1291-4.27660.33321330.31342604273794
4.2766-4.44770.28081230.28332614273795
4.4477-4.650.27811260.25012628275494
4.65-4.89490.27641670.24862583275094
4.8949-5.20130.24031220.24472628275094
5.2013-5.60240.2471430.23382603274693
5.6024-6.16530.23421460.25362592273893
6.1653-7.05520.27761470.25162624277193
7.0552-8.88050.25731480.25092598274692
8.8805-49.57310.3191360.29582687282390

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