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- EMDB-41577: mGluR3 in the presence of the antagonist LY 341495 and positive a... -

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Basic information

Entry
Database: EMDB / ID: EMD-41577
TitlemGluR3 in the presence of the antagonist LY 341495 and positive allosteric modulator VU6023326
Map dataFull length map
Sample
  • Complex: Metabotropic Glutamate Receptor 3 dimer
    • Protein or peptide: Metabotropic glutamate receptor 3
  • Ligand: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine
KeywordsGPCR / synaptic protein / MEMBRANE PROTEIN
Function / homology
Function and homology information


Class C/3 (Metabotropic glutamate/pheromone receptors) / group II metabotropic glutamate receptor activity / G protein-coupled glutamate receptor signaling pathway / astrocyte projection / G alpha (i) signalling events / postsynaptic modulation of chemical synaptic transmission / calcium channel regulator activity / regulation of synaptic transmission, glutamatergic / sensory perception of pain / modulation of chemical synaptic transmission ...Class C/3 (Metabotropic glutamate/pheromone receptors) / group II metabotropic glutamate receptor activity / G protein-coupled glutamate receptor signaling pathway / astrocyte projection / G alpha (i) signalling events / postsynaptic modulation of chemical synaptic transmission / calcium channel regulator activity / regulation of synaptic transmission, glutamatergic / sensory perception of pain / modulation of chemical synaptic transmission / presynaptic membrane / gene expression / scaffold protein binding / postsynaptic membrane / dendritic spine / postsynaptic density / neuron projection / axon / glutamatergic synapse / plasma membrane
Similarity search - Function
GPCR, family 3, metabotropic glutamate receptor 3 / 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, metabotropic glutamate receptor 3 / 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 / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Metabotropic glutamate receptor 3
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsStrauss A / Levitz J
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)1F31NS129320 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)F32GM148001 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01NS129904 United States
CitationJournal: bioRxiv / Year: 2023
Title: Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization.
Abstract: The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) ...The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted either at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric TMD-targeting compounds as therapeutics, an understanding of the functional and structural basis of their effects on mGluRs is limited. Here we use a battery of approaches to dissect the distinct functional and structural effects of orthosteric versus allosteric ligands. We find using electrophysiological and live cell imaging assays that both agonists and positive allosteric modulators (PAMs) can drive activation and desensitization of mGluRs. The effects of PAMs are pleiotropic, including both the ability to boost the maximal response to orthosteric agonists and to serve independently as desensitization-biased agonists across mGluR subtypes. Conformational sensors reveal PAM-driven inter-subunit re-arrangements at both the LBD and TMD. Motivated by this, we determine cryo-electron microscopy structures of mGluR3 in the presence of either an agonist or antagonist alone or in combination with a PAM. These structures reveal PAM-driven re-shaping of intra- and inter-subunit conformations and provide evidence for a rolling TMD dimer interface activation pathway that controls G protein and beta-arrestin coupling.
HIGHLIGHTS: -Agonists and PAMs drive mGluR activation, desensitization, and endocytosis-PAMs are desensitization-biased and synergistic with agonists-Four combinatorial ligand conditions reveal an ...HIGHLIGHTS: -Agonists and PAMs drive mGluR activation, desensitization, and endocytosis-PAMs are desensitization-biased and synergistic with agonists-Four combinatorial ligand conditions reveal an ensemble of full-length mGluR structures with novel interfaces-Activation and desensitization involve rolling TMD interfaces which are re-shaped by PAM.
History
DepositionAug 9, 2023-
Header (metadata) releaseJul 31, 2024-
Map releaseJul 31, 2024-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41577.png

Downloads & links

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Map

FileDownload / File: emd_41577.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull length map
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 416 pix.
= 343.2 Å		0.83 Å/pix.
x 416 pix.
= 343.2 Å		0.83 Å/pix.
x 416 pix.
= 343.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.283
Minimum - Maximum-0.8155589 - 1.4455216
Average (Standard dev.)0.0017863289 (±0.029191302)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 343.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Half map A of the transmembrane domain following particle subtraction

Fileemd_41577_additional_1.map
AnnotationHalf map A of the transmembrane domain following particle subtraction
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Additional map: Half map B of the transmembrane domain following particle subtraction

Fileemd_41577_additional_2.map
AnnotationHalf map B of the transmembrane domain following particle subtraction
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Additional map: Locally refined map of the extracellular domain

Fileemd_41577_additional_3.map
AnnotationLocally refined map of the extracellular domain
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Additional map: Map of the transmembrane domain following particle subtraction

Fileemd_41577_additional_4.map
AnnotationMap of the transmembrane domain following particle subtraction
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Additional map: Half map A for the locally refined extracellular domain

Fileemd_41577_additional_5.map
AnnotationHalf map A for the locally refined extracellular domain
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Additional map: Half map B for the locally refined extracellular domain

Fileemd_41577_additional_6.map
AnnotationHalf map B for the locally refined extracellular domain
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Half map: Half map A for full length map

Fileemd_41577_half_map_1.map
AnnotationHalf map A for full length map
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Half map: Half map B for full length map

Fileemd_41577_half_map_2.map
AnnotationHalf map B for full length map
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Sample components

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Entire : Metabotropic Glutamate Receptor 3 dimer

EntireName: Metabotropic Glutamate Receptor 3 dimer
Components
  • Complex: Metabotropic Glutamate Receptor 3 dimer
    • Protein or peptide: Metabotropic glutamate receptor 3
  • Ligand: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine

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Supramolecule #1: Metabotropic Glutamate Receptor 3 dimer

SupramoleculeName: Metabotropic Glutamate Receptor 3 dimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 260 KDa

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Macromolecule #1: Metabotropic glutamate receptor 3

MacromoleculeName: Metabotropic glutamate receptor 3 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 103.161555 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKMLTRLQIL MLALFSKGFL LSLGDHNFMR REIKIEGDLV LGGLFPINEK GTGTEECGRI NEDRGIQRLE AMLFAIDEIN KDNYLLPGV KLGVHILDTC SRDTYALEQS LEFVRASLTK VDEAEYMCPD GSYAIQENIP LLIAGVIGGS YSSVSIQVAN L LRLFQIPQ ...String:
MKMLTRLQIL MLALFSKGFL LSLGDHNFMR REIKIEGDLV LGGLFPINEK GTGTEECGRI NEDRGIQRLE AMLFAIDEIN KDNYLLPGV KLGVHILDTC SRDTYALEQS LEFVRASLTK VDEAEYMCPD GSYAIQENIP LLIAGVIGGS YSSVSIQVAN L LRLFQIPQ ISYASTSAKL SDKSRYDYFA RTVPPDFYQA KAMAEILRFF NWTYVSTVAS EGDYGETGIE AFEQEARLRN IC IATAEKV GRSNIRKSYD SVIRELLQKP NARVVVLFMR SDDSRELIAA ANRVNASFTW VASDGWGAQE SIVKGSEHVA YGA ITLELA SHPVRQFDRY FQSLNPYNNH RNPWFRDFWE QKFQCSLQNK RNHRQVCDKH LAIDSSNYEQ ESKIMFVVNA VYAM AHALH KMQRTLCPNT TKLCDAMKIL DGKKLYKEYL LKINFTAPFN PNKGADSIVK FDTFGDGMGR YNVFNLQQTG GKYSY LKVG HWAETLSLDV DSIHWSRNSV PTSQCSDPCA PNEMKNMQPG DVCCWICIPC EPYEYLVDEF TCMDCGPGQW PTADLS GCY NLPEDYIKWE DAWAIGPVTI ACLGFLCTCI VITVFIKHNN TPLVKASGRE LCYILLFGVS LSYCMTFFFI AKPSPVI CA LRRLGLGTSF AICYSALLTK TNCIARIFDG VKNGAQRPKF ISPSSQVFIC LGLILVQIVM VSVWLILETP GTRRYTLP E KRETVILKCN VKDSSMLISL TYDVVLVILC TVYAFKTRKC PENFNEAKFI GFTMYTTCII WLAFLPIFYV TSSDYRVQT TTMCISVSLS GFVVLGCLFA PKVHIVLFQP QKNVVTHRLH LNRFSVSGTA TTYSQSSAST YVPTVCNGRE VLDSTTSSLA GLVPRGSAA AKSAWSHPQF EKGGGSGGGS GGGSWSHPQF EK

UniProtKB: Metabotropic glutamate receptor 3

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Macromolecule #2: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine

MacromoleculeName: 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine
type: ligand / ID: 2 / Number of copies: 2 / Formula: Z99
Molecular weightTheoretical: 353.369 Da
Chemical component information

ChemComp-Z99:
2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine / antidepressant, antagonist*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation #1

Preparation ID1
Concentration4.5 mg/mL
BufferpH: 7.5
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Film type ID: 1 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Sample preparation #2

Preparation ID2
BufferpH: 7.5
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Film type ID: 1 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Detector mode: COUNTING / Average electron dose: 58.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.7000000000000001 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7wi6

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 116376
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-8trc:
mGluR3 in the presence of the antagonist LY 341495 and positive allosteric modulator VU6023326

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