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- PDB-6ffh: Crystal Structure of mGluR5 in complex with Fenobam at 2.65 A -

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Basic information

Entry
Database: PDB / ID: 6ffh
TitleCrystal Structure of mGluR5 in complex with Fenobam at 2.65 A
ComponentsMetabotropic glutamate receptor 5,Endolysin
KeywordsMEMBRANE PROTEIN / 7TM / RECEPTOR / GPCR / MEMBRANE-PROTEIN / SIGNALING PROTEIN
Function / homology
Function and homology information


A2A adenosine receptor binding / 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 / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / G protein-coupled glutamate receptor signaling pathway / astrocyte projection ...A2A adenosine receptor binding / 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 / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / G protein-coupled glutamate receptor signaling pathway / astrocyte projection / Class C/3 (Metabotropic glutamate/pheromone receptors) / : / glutamate receptor activity / Neurexins and neuroligins / protein tyrosine kinase activator activity / : / viral release from host cell by cytolysis / regulation of synaptic transmission, glutamatergic / peptidoglycan catabolic process / protein tyrosine kinase binding / dendritic shaft / learning / locomotory behavior / G protein-coupled receptor activity / postsynaptic density membrane / synapse organization / Schaffer collateral - CA1 synapse / cognition / cellular response to amyloid-beta / cell wall macromolecule catabolic process / lysozyme / lysozyme activity / G alpha (q) signalling events / chemical synaptic transmission / host cell cytoplasm / positive regulation of MAPK cascade / dendritic spine / learning or memory / defense response to bacterium / glutamatergic synapse / dendrite / 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 / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / Lysozyme-like domain superfamily
Similarity search - Domain/homology
Chem-D7W / OLEIC ACID / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / Endolysin / Metabotropic glutamate receptor 5
Similarity search - Component
Biological speciesHomo sapiens (human)
Enterobacteria phage T4 (virus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.65 Å
AuthorsChristopher, J.A. / Orgovan, Z. / Congreve, M. / Dore, A.S. / Errey, J.C. / Marshall, F.H. / Mason, J.S. / Okrasa, K. / Rucktooa, P. / Serrano-Vega, M.J. ...Christopher, J.A. / Orgovan, Z. / Congreve, M. / Dore, A.S. / Errey, J.C. / Marshall, F.H. / Mason, J.S. / Okrasa, K. / Rucktooa, P. / Serrano-Vega, M.J. / Ferenczy, G.G. / Keseru, G.M.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Structure-Based Optimization Strategies for G Protein-Coupled Receptor (GPCR) Allosteric Modulators: A Case Study from Analyses of New Metabotropic Glutamate Receptor 5 (mGlu5) X-ray Structures.
Authors: Christopher, J.A. / Orgovan, Z. / Congreve, M. / Dore, A.S. / Errey, J.C. / Marshall, F.H. / Mason, J.S. / Okrasa, K. / Rucktooa, P. / Serrano-Vega, M.J. / Ferenczy, G.G. / Keseru, G.M.
History
DepositionJan 8, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 7, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 14, 2018Group: Database references / Structure summary / Category: citation / citation_author / entity
Item: _citation.title / _citation_author.name ..._citation.title / _citation_author.name / _entity.details / _entity.pdbx_fragment / _entity.pdbx_mutation
Revision 1.2Mar 28, 2018Group: Data collection / Database references / Category: citation / Item: _citation.title
Revision 1.3Apr 24, 2019Group: Data collection / Database references / Source and taxonomy
Category: citation / database_PDB_rev ...citation / database_PDB_rev / database_PDB_rev_record / entity_src_gen / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _entity_src_gen.pdbx_host_org_cell_line
Revision 1.4Jan 17, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Metabotropic glutamate receptor 5,Endolysin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,0909
Polymers49,8601
Non-polymers2,2318
Water23413
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Protein elutes as a monomer on size exclusion chromatography.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2860 Å2
ΔGint15 kcal/mol
Surface area21130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)143.217, 43.478, 82.383
Angle α, β, γ (deg.)90.000, 99.220, 90.000
Int Tables number5
Space group name H-MC121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Metabotropic glutamate receptor 5,Endolysin / mGluR5 / Lysis protein / Lysozyme / Muramidase


Mass: 49859.586 Da / Num. of mol.: 1 / Fragment: MGLUR5 / Mutation: C54T C97A E579A N667Y I669A G675M T742A S753A
Source method: isolated from a genetically manipulated source
Details: Chimeric construct of Human mGLU5 (GRM5) with a Bacteriophage T4 Lysozyme (P00720) insertion in intracellular loop 2 between residues LYS678 and LYS679.
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Enterobacteria phage T4 (virus)
Gene: GRM5, GPRC1E, MGLUR5 / Cell line (production host): Sf21 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41594, UniProt: P00720, lysozyme

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Non-polymers , 5 types, 21 molecules

#2: Chemical
ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 5 / Fragment: T4L / Mutation: C54T C97A
Source method: isolated from a genetically manipulated source
Formula: C18H34O2 / References: lysozyme
#3: Chemical ChemComp-MES / 2-(N-MORPHOLINO)-ETHANESULFONIC ACID


Mass: 195.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H13NO4S / Comment: pH buffer*YM
#4: Chemical ChemComp-D7W / 1-(3-chlorophenyl)-3-(3-methyl-5-oxidanylidene-4~{H}-imidazol-2-yl)urea


Mass: 266.684 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H11ClN4O2 / Comment: antagonist*YM
#5: Chemical ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H40O4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / Source method: isolated from a natural source / Formula: H2O

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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: 2.68 Å3/Da / Density % sol: 54.04 % / Mosaicity: 0.17 °
Crystal growTemperature: 293.1 K / Method: lipidic cubic phase / pH: 6.8
Details: 24-34% V/V PEG400, 0.2 M AMMONIUM PHOSPHATE DIBASIC, 0.1 M MES, PH 6.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96862 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 27, 2014
RadiationMonochromator: SI / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96862 Å / Relative weight: 1
ReflectionResolution: 2.65→34.5 Å / Num. obs: 13189 / % possible obs: 88.8 % / Redundancy: 2.7 % / Biso Wilson estimate: 42.567 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.156 / Rpim(I) all: 0.101 / Rrim(I) all: 0.187 / Net I/σ(I): 6.6 / Num. measured all: 36238 / Scaling rejects: 21
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.65-2.782.70.89318120.5880.5821.07392
8.79-34.52.90.0463520.9970.0270.05479.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
Aimless0.2.17data scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4OO9

4oo9


Resolution: 2.65→34.496 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 27.98
RfactorNum. reflection% reflection
Rfree0.2669 702 5.37 %
Rwork0.2435 --
obs0.2447 13073 87.73 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 141.11 Å2 / Biso mean: 51.0754 Å2 / Biso min: 20.81 Å2
Refinement stepCycle: final / Resolution: 2.65→34.496 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3233 0 125 13 3371
Biso mean--64.08 34.69 -
Num. residues----414
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023418
X-RAY DIFFRACTIONf_angle_d0.4434606
X-RAY DIFFRACTIONf_chiral_restr0.036531
X-RAY DIFFRACTIONf_plane_restr0.003563
X-RAY DIFFRACTIONf_dihedral_angle_d13.7062055
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.6501-2.85460.35891400.32452515265590
2.8546-3.14170.30081530.28642478263189
3.1417-3.59590.3291300.25772431256187
3.5959-4.52880.22251270.21832485261288
4.5288-34.49880.23061520.21692462261485
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.5543-0.1201-0.31841.679-0.53061.7860.0690.0647-0.2065-0.0583-0.01480.0432-0.0364-0.1055-0.06020.1877-0.0433-0.03620.1919-0.00730.3177-25.215513.397239.8191
23.428-0.40180.62121.24740.4222.5885-0.3314-0.60380.34970.120.05850.1434-0.3017-0.43740.23660.31820.06350.00880.4581-0.03330.3298-13.599629.85931.7566
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A568 - 678
2X-RAY DIFFRACTION1A1679 - 1832
3X-RAY DIFFRACTION2A1002 - 1161

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