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- PDB-7p2l: thermostabilised 7TM domain of human mGlu5 receptor bound to phot... -

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Basic information

Entry
Database: PDB / ID: 7p2l
Titlethermostabilised 7TM domain of human mGlu5 receptor bound to photoswitchable ligand alloswitch-1
ComponentsMetabotropic glutamate receptor 5,Endolysin,Metabotropic glutamate receptor 5
KeywordsSIGNALING PROTEIN / G protein coupled receptor / mGlu5 7TM / photoswitchable ligand / allosteric modulator
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-4YI / Endolysin / Metabotropic glutamate receptor 5
Similarity search - Component
Biological speciesHomo sapiens (human)
Enterobacteria phage T4 (virus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.54 Å
AuthorsHuang, C.Y. / Vinothkumar, K.R. / Lebon, G.
Funding support France, 2items
OrganizationGrant numberCountry
Centre National de la Recherche Scientifique (CNRS)ATIP AVENIR France
Agence Nationale de la Recherche (ANR)ANR-20-CE11-0019 France
CitationJournal: Cell Rep / Year: 2021
Title: Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations.
Authors: Chady Nasrallah / Giuseppe Cannone / Julie Briot / Karine Rottier / Alice E Berizzi / Chia-Ying Huang / Robert B Quast / Francois Hoh / Jean-Louis Banères / Fanny Malhaire / Ludovic Berto / ...Authors: Chady Nasrallah / Giuseppe Cannone / Julie Briot / Karine Rottier / Alice E Berizzi / Chia-Ying Huang / Robert B Quast / Francois Hoh / Jean-Louis Banères / Fanny Malhaire / Ludovic Berto / Anaëlle Dumazer / Joan Font-Ingles / Xavier Gómez-Santacana / Juanlo Catena / Julie Kniazeff / Cyril Goudet / Amadeu Llebaria / Jean-Philippe Pin / Kutti R Vinothkumar / Guillaume Lebon /
Abstract: Metabotropic glutamate receptors (mGluRs) are dimeric G-protein-coupled receptors activated by the main excitatory neurotransmitter, L-glutamate. mGluR activation by agonists binding in the venus ...Metabotropic glutamate receptors (mGluRs) are dimeric G-protein-coupled receptors activated by the main excitatory neurotransmitter, L-glutamate. mGluR activation by agonists binding in the venus flytrap domain is regulated by positive (PAM) or negative (NAM) allosteric modulators binding to the 7-transmembrane domain (7TM). We report the cryo-electron microscopy structures of fully inactive and intermediate-active conformations of mGlu receptor bound to an antagonist and a NAM or an agonist and a PAM, respectively, as well as the crystal structure of the 7TM bound to a photoswitchable NAM. The agonist induces a large movement between the subunits, bringing the 7TMs together and stabilizing a 7TM conformation structurally similar to the inactive state. Using functional approaches, we demonstrate that the PAM stabilizes a 7TM active conformation independent of the conformational changes induced by agonists, representing an alternative mode of mGlu activation. These findings provide a structural basis for different mGluR activation modes.
History
DepositionJul 6, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 8, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)52,2852
Polymers51,9181
Non-polymers3671
Water1267
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area20850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.690, 43.400, 82.120
Angle α, β, γ (deg.)90.000, 99.380, 90.000
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: 51918.055 Da / Num. of mol.: 1 / Mutation: E579A,N667Y,I669A,G675M,T742A,S753A
Source method: isolated from a genetically manipulated source
Details: The macromolecule is a chimera of mGluR TMD and T4 lysozyme. The Uniprot ID of mGluR5 is P41594 and the T4 lysozyme if P00720. The lysozyme sequence is inserted between residue 678 and 679 ...Details: The macromolecule is a chimera of mGluR TMD and T4 lysozyme. The Uniprot ID of mGluR5 is P41594 and the T4 lysozyme if P00720. The lysozyme sequence is inserted between residue 678 and 679 of mGluR5. In the PDB, the lysozyme is numbered from 1002-1162 (Asn & Tyr). The gaps are between 680-688 and 721-728. Residues 644 & 733 form a disuphide bond. The lysozyme has also been engineered and has the following mutations. C54T (in PDB it is 1054) and C97T (in PDB it is 1097).
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Enterobacteria phage T4 (virus)
Gene: GRM5, GPRC1E, MGLUR5 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P41594, UniProt: P00720, lysozyme
#2: Chemical ChemComp-4YI / 2-chloranyl-~{N}-[2-methoxy-4-[(~{E})-pyridin-2-yldiazenyl]phenyl]benzamide


Mass: 366.801 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15ClN4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.72 Å3/Da / Density % sol: 54.83 %
Crystal growTemperature: 295 K / Method: lipidic cubic phase
Details: 0.15-0.25 M ammonium phosphate dibasic, 22-24 % polyethylene glycol 400, either with 0.10 M 2-(N-morpholino)ethanesulfonic acid (MES) pH 6.7-6.8 or 0.1 M HEPES pH 6.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 14, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.54→49.11 Å / Num. obs: 16595 / % possible obs: 100 % / Redundancy: 10.66 % / CC1/2: 0.997 / Rrim(I) all: 0.253 / Net I/σ(I): 6.35
Reflection shellResolution: 2.54→2.61 Å / Redundancy: 9.3 % / Num. unique obs: 1184 / CC1/2: 0.51 / Rrim(I) all: 2.685 / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XSCALEVERSION Jan 31, 2020 BUILT=20200417data scaling
PDB_EXTRACT3.27data extraction
XDSVERSION Jan 31, 2020 BUILT=20200417data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4oo9

4oo9


Resolution: 2.54→49.11 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.881 / SU B: 17.497 / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.647 / ESU R Free: 0.336 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2853 830 5 %RANDOM
Rwork0.2267 ---
obs0.2298 15764 99.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 149.46 Å2 / Biso mean: 69.807 Å2 / Biso min: 46.68 Å2
Baniso -1Baniso -2Baniso -3
1--3.72 Å20 Å2-2.45 Å2
2--8.63 Å20 Å2
3----3.88 Å2
Refinement stepCycle: final / Resolution: 2.54→49.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3238 0 26 7 3271
Biso mean--57.46 60.09 -
Num. residues----414
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0133332
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173293
X-RAY DIFFRACTIONr_angle_refined_deg1.3061.6494520
X-RAY DIFFRACTIONr_angle_other_deg1.1151.5767534
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9365411
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.43820.903144
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.73315567
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.1621521
X-RAY DIFFRACTIONr_chiral_restr0.0530.2457
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023684
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02787
LS refinement shellResolution: 2.54→2.606 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.412 59 -
Rwork0.387 1117 -
all-1176 -
obs--99.92 %

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