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- PDB-6n50: Metabotropic Glutamate Receptor 5 Extracellular Domain in Complex... -

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Basic information

Entry
Database: PDB / ID: 6n50
TitleMetabotropic Glutamate Receptor 5 Extracellular Domain in Complex with Nb43 and L-quisqualic acid
Components
  • Metabotropic glutamate receptor 5
  • Nanobody 43Single-domain antibody
KeywordsSIGNALING 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
Chem-QUS / Metabotropic glutamate receptor 5
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.751 Å
AuthorsKoehl, A. / Hu, H. / Feng, D. / Sun, B. / Chu, M. / Weis, W.I. / Skiniotis, G. / 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.pdbx_role
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
C: Metabotropic glutamate receptor 5
E: Nanobody 43
hetero molecules


Theoretical massNumber of molelcules
Total (without water)217,21512
Polymers215,5424
Non-polymers1,6738
Water0
1
A: Metabotropic glutamate receptor 5
E: Nanobody 43
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,3825
Polymers80,7502
Non-polymers6323
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2290 Å2
ΔGint-8 kcal/mol
Surface area27410 Å2
MethodPISA
2
B: Metabotropic glutamate receptor 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8063
Polymers67,3961
Non-polymers4102
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area570 Å2
ΔGint-5 kcal/mol
Surface area18170 Å2
MethodPISA
3
C: Metabotropic glutamate receptor 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,0274
Polymers67,3961
Non-polymers6323
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area750 Å2
ΔGint-2 kcal/mol
Surface area23010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)150.433, 157.159, 208.112
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number24
Space group name H-MI212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 25 through 67 or (resid 68...
21(chain C and (resid 25 through 116 or resid 141...

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
11ARGARGGLNGLN(chain A and (resid 25 through 67 or (resid 68...AA25 - 6742 - 84
12ARGARGARGARG(chain A and (resid 25 through 67 or (resid 68...AA6885
13ARGARGPROPRO(chain A and (resid 25 through 67 or (resid 68...AA25 - 56942 - 586
14ARGARGPROPRO(chain A and (resid 25 through 67 or (resid 68...AA25 - 56942 - 586
15ARGARGPROPRO(chain A and (resid 25 through 67 or (resid 68...AA25 - 56942 - 586
16ARGARGPROPRO(chain A and (resid 25 through 67 or (resid 68...AA25 - 56942 - 586
21ARGARGSERSER(chain C and (resid 25 through 116 or resid 141...CC25 - 11642 - 133
22LYSLYSPHEPHE(chain C and (resid 25 through 116 or resid 141...CC141 - 185158 - 202
23LYSLYSLYSLYS(chain C and (resid 25 through 116 or resid 141...CC186203
24ARGARGPROPRO(chain C and (resid 25 through 116 or resid 141...CC25 - 56942 - 586
25ARGARGPROPRO(chain C and (resid 25 through 116 or resid 141...CC25 - 56942 - 586
26ARGARGPROPRO(chain C and (resid 25 through 116 or resid 141...CC25 - 56942 - 586
27ARGARGPROPRO(chain C and (resid 25 through 116 or resid 141...CC25 - 56942 - 586

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Components

#1: Protein Metabotropic glutamate receptor 5 / / mGluR5


Mass: 67395.633 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GRM5, GPRC1E, MGLUR5 / Plasmid: pACGP67 / Cell line (production host): High Five / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P41594
#2: Antibody Nanobody 43 / Single-domain antibody


Mass: 13354.672 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Plasmid: PE SUMO / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3)
#3: 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.: 5
Source method: isolated from a genetically manipulated source
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
#4: Chemical ChemComp-QUS / (S)-2-AMINO-3-(3,5-DIOXO-[1,2,4]OXADIAZOLIDIN-2-YL)-PROPIONIC ACID / QUISQUALATE / Quisqualic acid


Mass: 189.126 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C5H7N3O5 / Comment: agonist*YM

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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: 3.1 Å3/Da / Density % sol: 60.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 100 mM NaCl 50 mM ADA pH 7.0 20% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.97946 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 9, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 3.75→39.29 Å / Num. obs: 25207 / % possible obs: 98.6 % / Redundancy: 3.4 % / CC1/2: 0.916 / Rmerge(I) obs: 0.123 / Rpim(I) all: 0.08 / Rrim(I) all: 0.147 / Net I/σ(I): 8.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
3.75-4.013.40.84844870.7860.541.0198.1
10.61-39.293.10.02611730.9970.0180.03296.5

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Processing

Software
NameVersionClassification
PHENIX1.14_3211refinement
Aimless0.7.1data scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3LMK

3lmk


Resolution: 3.751→39.29 Å / SU ML: 0.59 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 34.03
RfactorNum. reflection% reflection
Rfree0.3001 1996 7.94 %
Rwork0.2657 --
obs0.2683 25151 98.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 249.2 Å2 / Biso mean: 151.3731 Å2 / Biso min: 85.83 Å2
Refinement stepCycle: final / Resolution: 3.751→39.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12039 0 109 0 12148
Biso mean--175.75 --
Num. residues----1596
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A4514X-RAY DIFFRACTION7.228TORSIONAL
12C4514X-RAY DIFFRACTION7.228TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3.7515-3.84520.42831450.36591577172296
3.8452-3.94910.3851370.33441654179199
3.9491-4.06520.34481490.31541634178399
4.0652-4.19620.32631260.29871660178699
4.1962-4.3460.32571350.27441649178499
4.346-4.51980.27211450.25241648179399
4.5198-4.72520.31371390.24471648178798
4.7252-4.97380.27281450.2531600174597
4.9738-5.28480.31381340.24951653178799
5.2848-5.69170.26891520.270316821834100
5.6917-6.26240.2941580.26811663182199
6.2624-7.16380.30451460.27871659180598
7.1638-9.00770.26291290.23481685181498
9.0077-39.29190.29021560.2521743189997
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)
13.552-0.0291-0.66180.68850.00110.6072-0.14420.13540.2313-0.13570.1621-0.1330.0437-0.1246-0.0179-0.1313-0.06850.1174-0.0221-0.0747-0.127911.189621.3282-15.0843
22.26260.11960.8082.6513-0.07580.3399-0.0583-0.03780.33730.2540.0064-0.2089-0.1477-0.36890.05190.26250.1520.0016-0.3040.1512-0.1217-1.496918.834154.3304
31.5334-0.2723-0.07071.54610.38070.3443-0.1149-0.024-0.5380.12160.1089-0.23850.47060.18690.006-0.03-0.07230.152-0.2673-0.09960.290319.3552-14.0667-20.3686
44.10651.9829-0.89384.2285-2.04181.1487-0.0218-0.0593-0.01140.0332-0.0043-0.01220.1226-0.03610.0262-0.21370.06820.11480.07320.14860.1218-29.163412.71549.7051
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A25 - 569
2X-RAY DIFFRACTION2{ B|* }B23 - 496
3X-RAY DIFFRACTION3{ C|* }C25 - 569
4X-RAY DIFFRACTION4{ E|* }E3 - 125

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