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- EMDB-44861: metabotropic glutamate receptor subtype three bound to the antago... -

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Basic information

Entry
Database: EMDB / ID: EMD-44861
Titlemetabotropic glutamate receptor subtype three bound to the antagonist LY 341495, class two
Map dataFull length map
Sample
  • Complex: Metabotropic Glutamate Receptor 3 dimer
    • Protein or peptide: metabotropic glutamate receptor
KeywordsGPCR / synaptic protein / MEMBRANE PROTEIN
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
DepositionMay 13, 2024-
Header (metadata) releaseJul 31, 2024-
Map releaseJul 31, 2024-
UpdateJul 31, 2024-
Current statusJul 31, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44861.png

Downloads & links

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Map

FileDownload / File: emd_44861.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
Contrast
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: 0.22
Minimum - Maximum-0.772548 - 1.4933819
Average (Standard dev.)0.00043557296 (±0.030077275)
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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Half map: Half map B

Fileemd_44861_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_44861_half_map_2.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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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

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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: all
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 260 KDa

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Macromolecule #1: metabotropic glutamate receptor

MacromoleculeName: metabotropic glutamate receptor / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
SequenceString: atgaagatgt tgacaagact acaaattctt atgttagctt tgttttcaaa gggattttta ctctctttag gagatcacaa ctttatgagg agggaaatta aaatagaagg agaccttgtt ttaggaggct tatttcctat taatgaaaaa ggcactggaa ctgaagagtg ...String:
atgaagatgt tgacaagact acaaattctt atgttagctt tgttttcaaa gggattttta ctctctttag gagatcacaa ctttatgagg agggaaatta aaatagaagg agaccttgtt ttaggaggct tatttcctat taatgaaaaa ggcactggaa ctgaagagtg tgggcgaatc aatgaagacc gaggtatcca acgcctggag gccatgttgt ttgccatcga cgagattaac aaagacaatt acttgctccc aggagtgaag ctgggtgttc atattttgga tacatgttca agggatacct atgcattaga gcaatcactg gagtttgtca gggcatcttt gactaaagtg gatgaagccg agtatatgtg tcctgatgga tcatatgcta ttcaagaaaa catcccactg ctcattgcag gagtcattgg tggttcatac agcagtgttt ccatacaggt ggcaaacctg ctgaggctct tccagatccc tcagataagc tacgcctcca ccagcgccaa actcagtgac aagtcgcgct atgattactt tgccaggacc gtgccccctg acttctacca ggccaaagcc atggccgaga tcttgcgctt cttcaactgg acctatgtgt ccaccgttgc ctctgagggt gactatgggg agacagggat tgaggccttc gagcaggaag cacggctgcg taacatctgc atcgccactg ctgaaaaggt gggccgctcc aacatccgca agtcctacga cagcgtgata cgtgagctcc tgcagaaacc caatgcgcgg gtcgtggtcc tgttcatgcg cagtgacgac tcacgagagc tgatcgcggc agccaaccgc gtgaatgcct ccttcacctg ggtggccagc gacggctggg gtgctcagga gagcatagtc aagggcagtg agcatgtagc ctatggcgcc atcacccttg agctggcatc tcacccggtt cgccagtttg atcgctactt ccagagcctc aacccctaca acaatcatcg taacccctgg ttccgagact tctgggagca gaagttccag tgcagcctcc agaacaagag aaaccacaga caggtttgtg acaagcacct ggccattgac agcagcaact atgagcaaga atccaagatt atgtttgtgg tgaatgcagt gtacgccatg gcgcatgcgc tgcacaaaat gcagcgcacc ctctgtccca acaccaccaa gctctgtgat gcaatgaaga tcctagatgg aaagaaattg tacaaggagt atttgctgaa aatcaacttc acagctccat tcaacccaaa taaaggagca gacagcattg tgaagtttga cacttttgga gacgggatgg gaagatacaa cgtgttcaac ttgcagcaga caggtgggaa gtattcttac ttgaaggttg gccactgggc agaaaccttg tctctagatg tggactctat ccattggtcc cggaactcag tccccacttc ccagtgcagt gatccctgtg ccccgaatga aatgaagaac atgcagcccg gggatgtttg ctgctggatc tgtatcccct gtgagcccta tgaatacctg gtcgatgagt tcacctgtat ggattgtggc cctggccagt ggcccactgc agacctatct ggatgctaca accttccaga ggattacatc aaatgggaag acgcctgggc aataggcccg gtcaccattg cctgcctggg ctttctgtgt acatgcatag ttataactgt ttttatcaag cacaacaaca cacccttggt caaagcatca ggtcgagaac tctgctacat cttgttattt ggagttagcc tgtcctattg catgacattc ttcttcattg ctaagccatc gcctgtcatc tgtgcgttgc gccgacttgg gcttgggacc tctttcgcca tctgttattc agcgctgctg accaagacaa actgcattgc tcgcatcttc gatggggtca agaacggcgc tcagaggccg aaattcatca gccccagttc tcaggttttt atttgcctgg gtttgatact ggtgcaaatt gtgatggtgt ccgtgtggct tatcctggag actccaggta ctagaagata cacccttcca gagaagcggg aaacagtcat cctgaaatgc aatgtcaaag attccagcat gttgatctct ctgacctatg acgtggtcct ggtgatccta tgcactgtgt atgccttcaa aacgaggaag tgtcctgaaa acttcaatga agccaagttt ataggcttca ccatgtacac cacctgcatc atctggttgg cattcctccc tatattttat gtgacatcaa gtgactacag agtgcagacg acaacaatgt gcatctccgt tagcctgagc ggtttcgtgg tcttgggctg tttgtttgcc cccaaggtgc acatcgtcct gttccaaccc cagaagaatg tggtcacaca cagacttcac ctcaacaggt tcagcgtcag cggaactgca accacctatt ctcagtcctc tgcaagcaca tatgtcccaa cagtgtgcaa cggaagggaa gtcctggact ccaccacctc atctctgGCA GGACTGGTGC CGCGCGGCTC TGCGGCGGCC GCCATGGTGA GCAAGGGCGA GGAGCTGTTC ACCGGGGTGG TGCCCATCCT GGTCGAGCTG GACGGCGACG TAAACGGCCA CAAGTTCAGC GTGTCCGGCG AGGGCGAGGG CGATGCCACC TACGGCAAGC TGACCCTGAA GCTGATCTGC ACCACCGGCA AGCTGCCCGT GCCCTGGCCC ACCCTCGTGA CCACCCTGGG CTACGGCCTG CAGTGCTTCG CCCGCTACCC CGACCACATG AAGCAGCACG ACTTCTTCAA GTCCGCCATG CCCGAAGGCT ACGTCCAGGA GCGCACCATC TTCTTCAAGG ACGACGGCAA CTACAAGACC CGCGCCGAGG TGAAGTTCGA GGGCGACACC CTGGTGAACC GCATCGAGCT GAAGGGCATC GACTTCAAGG AGGACGGCAA CATCCTGGGG CACAAGCTGG AGTACAACTA CAACAGCCAC AACGTCTATA TCACCGCCGA CAAGCAGAAG AACGGCATCA AGGCCAACTT CAAGATCCGC CACAACATCG AGGACGGCGG CGTGCAGCTC GCCGACCACT ACCAGCAGAA CACCCCCATC GGCGACGGCC CCGTGCTGCT GCCCGACAAC CACTACCTGA GCTACCAGTC CAAGCTGAGC AAAGACCCCA ACGAGAAGCG CGATCACATG GTCCTGCTGG AGTTCGTGAC CGCCGCCGGG ATCACTCTCG GCATGGACGA GCTGTACAAG TCTGCTTGGA GCCACCCGCA GTTCGAGAAA GGTGGAGGTT CCGGAGGTGG ATCGGGAGGT GGATCGTGGA GCCACCCGCA GTTCGAAAAA TGA

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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: Quantifoil / Support film - Film type ID: 1 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Sample preparation #2

Preparation ID2
BufferpH: 7.5
GridModel: Quantifoil / Support film - Film type ID: 1 / Support film - Material: GOLD / Support film - topology: HOLEY
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:

7mtr

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 80540
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

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