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- PDB-5cgd: Structure of the human class C GPCR metabotropic glutamate recept... -

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Basic information

Entry
Database: PDB / ID: 5cgd
TitleStructure of the human class C GPCR metabotropic glutamate receptor 5 transmembrane domain in complex with the negative allosteric modulator 3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile - (HTL14242)
ComponentsMetabotropic glutamate receptor 5,Endolysin,Metabotropic glutamate receptor 5
KeywordsSIGNALING PROTEIN / 7TM / Receptor / GPCR / Membrane-Protein
Function / homology
Function and homology information


A2A adenosine receptor binding / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / positive regulation of long-term neuronal synaptic plasticity / desensitization of G protein-coupled receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate receptor activity ...A2A adenosine receptor binding / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / G protein-coupled receptor activity involved in regulation of postsynaptic membrane potential / adenylate cyclase inhibiting G protein-coupled glutamate receptor activity / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / positive regulation of long-term neuronal synaptic plasticity / desensitization of G protein-coupled receptor signaling pathway / G protein-coupled glutamate receptor signaling pathway / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate receptor activity / Neurexins and neuroligins / astrocyte projection / protein tyrosine kinase activator activity / regulation of synaptic transmission, glutamatergic / viral release from host cell by cytolysis / peptidoglycan catabolic process / positive regulation of calcium-mediated signaling / 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 / dendritic spine / host cell cytoplasm / learning or memory / positive regulation of MAPK cascade / defense response to bacterium / neuronal cell body / dendrite / regulation of DNA-templated transcription / glutamatergic synapse / 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 3. / G-protein coupled receptors family 3 signature 2. / GPCR, family 3, nine cysteines domain ...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 3. / 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 / GPCR, family 3 / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / Lysozyme - #40 / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / Lysozyme / Lysozyme-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-51E / OLEIC ACID / Endolysin / Metabotropic glutamate receptor 5
Similarity search - Component
Biological speciesHomo sapiens (human)
Enterobacteria phage T4 (virus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.603 Å
AuthorsChristopher, J.A. / Aves, S.J. / Bennett, K.A. / Dore, A.S. / Errey, J.C. / Jazayeri, A. / Marshall, F.H. / Okrasa, K. / Serrano-Vega, M.J. / Tehan, B.G. ...Christopher, J.A. / Aves, S.J. / Bennett, K.A. / Dore, A.S. / Errey, J.C. / Jazayeri, A. / Marshall, F.H. / Okrasa, K. / Serrano-Vega, M.J. / Tehan, B.G. / Wiggin, G.R. / Congreve, M.
Citation
Journal: J.Med.Chem. / Year: 2015
Title: Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 Negative Allosteric Modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile).
Authors: Christopher, J.A. / Aves, S.J. / Bennett, K.A. / Dore, A.S. / Errey, J.C. / Jazayeri, A. / Marshall, F.H. / Okrasa, K. / Serrano-Vega, M.J. / Tehan, B.G. / Wiggin, G.R. / Congreve, M.
#1: Journal: Nature / Year: 2014
Title: Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain.
Authors: Dore, A.S. / Okrasa, K. / Patel, J.C. / Serrano-Vega, M. / Bennett, K. / Cooke, R.M. / Errey, J.C. / Jazayeri, A. / Khan, S. / Tehan, B. / Weir, M. / Wiggin, G.R. / Marshall, F.H.
History
DepositionJul 9, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Aug 12, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2015Group: Database references
Revision 1.2Dec 16, 2015Group: Database references / Derived calculations / Other
Revision 1.3Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
Revision 1.4Jan 10, 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
Revision 1.5Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)51,2436
Polymers49,8031
Non-polymers1,4415
Water1,17165
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1880 Å2
ΔGint9 kcal/mol
Surface area21050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)143.574, 43.727, 81.862
Angle α, β, γ (deg.)90.00, 98.97, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 49802.531 Da / Num. of mol.: 1
Mutation: E579A N667Y I669A G675M C1054T C1097A T742A S753A,E579A N667Y I669A G675M C1054T C1097A T742A S753A,E579A N667Y I669A G675M C1054T C1097A T742A S753A
Source method: isolated from a genetically manipulated source
Details: mGluR5 transmembrane domain from Homo Sapiens fused with T4-Lysozyme from Enterobacteria Phage T4 in complex with the new chemical entity (NCE): 3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile
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
#2: Chemical
ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H34O2
#3: Chemical ChemComp-51E / 3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile


Mass: 310.713 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H8ClFN4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 65 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.53 Å3/Da / Density % sol: 51.37 %
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: 200 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.96861 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 29, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96861 Å / Relative weight: 1
ReflectionResolution: 2.6→34.51 Å / Num. obs: 14891 / % possible obs: 95.3 % / Redundancy: 3.3 % / Biso Wilson estimate: 33.43 Å2 / Rmerge(I) obs: 0.152 / Net I/σ(I): 7
Reflection shellResolution: 2.6→2.72 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.723 / Mean I/σ(I) obs: 2 / % possible all: 96.5

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4OO9

4oo9


Resolution: 2.603→29.747 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 29.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2853 702 4.72 %Imported from 4OO9
Rwork0.2419 ---
obs0.244 14884 94.59 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 37 Å2
Refinement stepCycle: LAST / Resolution: 2.603→29.747 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3196 0 84 65 3345
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023344
X-RAY DIFFRACTIONf_angle_d0.6164515
X-RAY DIFFRACTIONf_dihedral_angle_d11.1161237
X-RAY DIFFRACTIONf_chiral_restr0.022524
X-RAY DIFFRACTIONf_plane_restr0.002549
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.603-2.80390.33771370.28892842X-RAY DIFFRACTION96
2.8039-3.08580.29791330.26422856X-RAY DIFFRACTION96
3.0858-3.53160.32481380.26152827X-RAY DIFFRACTION94
3.5316-4.44710.25311460.22072842X-RAY DIFFRACTION95
4.4471-29.74880.27231480.22332815X-RAY DIFFRACTION92

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