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- EMDB-23995: CryoEM Structure of Full-Length mGlu2 Bound to Ago-PAM ADX55164 a... -

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Basic information

Entry
Database: EMDB / ID: EMD-23995
TitleCryoEM Structure of Full-Length mGlu2 Bound to Ago-PAM ADX55164 and Glutamate
Map dataCryoEM Map of Full-Length mGlu2 Bound to Ago-PAM ADX55164 and Glutamate
Sample
  • Complex: Full-length mGlu2 in ago-PAM and L-Glutamate bound-state
    • Protein or peptide: Metabotropic glutamate receptor 2
  • Ligand: GLUTAMIC ACID
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 2-methoxy-6-propyl-N-(2-{4-[(1H-tetrazol-5-yl)methoxy]phenyl}ethyl)thieno[2,3-d]pyrimidin-4-amine
KeywordsMetabotropic Glutamate Receptor 2 (mGlu2) (mGluR2) / Family C G protein-coupled receptor (GPCR) / Heterotrimeric G protein / CryoEM structure / MEMBRANE PROTEIN / MEMBRANE PROTEIN-AGONIST complex
Function / homology
Function and homology information


regulation of response to drug / group II metabotropic glutamate receptor activity / intracellular glutamate homeostasis / behavioral response to nicotine / negative regulation of adenylate cyclase activity / G protein-coupled glutamate receptor signaling pathway / astrocyte projection / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate secretion / glutamate receptor activity ...regulation of response to drug / group II metabotropic glutamate receptor activity / intracellular glutamate homeostasis / behavioral response to nicotine / negative regulation of adenylate cyclase activity / G protein-coupled glutamate receptor signaling pathway / astrocyte projection / Class C/3 (Metabotropic glutamate/pheromone receptors) / glutamate secretion / glutamate receptor activity / regulation of glutamate secretion / long-term synaptic depression / regulation of dopamine secretion / calcium channel regulator activity / regulation of synaptic transmission, glutamatergic / presynaptic modulation of chemical synaptic transmission / response to cocaine / G protein-coupled receptor activity / presynaptic membrane / gene expression / G alpha (i) signalling events / scaffold protein binding / chemical synaptic transmission / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / axon / glutamatergic synapse / dendrite / plasma membrane
Similarity search - Function
GPCR, family 3, metabotropic glutamate receptor 2 / 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 2 / 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 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsSeven AB / Barros-Alvarez X
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS092695 United States
CitationJournal: Nature / Year: 2021
Title: G-protein activation by a metabotropic glutamate receptor.
Authors: Alpay B Seven / Ximena Barros-Álvarez / Marine de Lapeyrière / Makaía M Papasergi-Scott / Michael J Robertson / Chensong Zhang / Robert M Nwokonko / Yang Gao / Justin G Meyerowitz / Jean- ...Authors: Alpay B Seven / Ximena Barros-Álvarez / Marine de Lapeyrière / Makaía M Papasergi-Scott / Michael J Robertson / Chensong Zhang / Robert M Nwokonko / Yang Gao / Justin G Meyerowitz / Jean-Philippe Rocher / Dominik Schelshorn / Brian K Kobilka / Jesper M Mathiesen / Georgios Skiniotis /
Abstract: Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of ...Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric G. Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6-TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound G can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6-TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation.
History
DepositionMay 13, 2021-
Header (metadata) releaseJul 7, 2021-
Map releaseJul 7, 2021-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.1
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.1
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7mtr
  • Surface level: 0.1
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7mtr
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23995.png

Downloads & links

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Map

FileDownload / File: emd_23995.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM Map of Full-Length mGlu2 Bound to Ago-PAM ADX55164 and Glutamate
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.87 Å/pix.
x 448 pix.
= 388.73 Å		0.87 Å/pix.
x 448 pix.
= 388.73 Å		0.87 Å/pix.
x 448 pix.
= 388.73 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8677 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1 / Movie #1: 0.1
Minimum - Maximum-0.020635085 - 1.8109927
Average (Standard dev.)0.00072434446 (±0.016839268)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 388.72958 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.867700892857140.867700892857140.86770089285714
M x/y/z448448448
origin x/y/z0.0000.0000.000
length x/y/z388.730388.730388.730
α/β/γ90.00090.00090.000
start NX/NY/NZ-210-210-210
NX/NY/NZ420420420
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS448448448
D min/max/mean-0.0211.8110.001

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Supplemental data

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Additional map: Local and focused refinement of mGlu2 CRD and 7TM domains

Fileemd_23995_additional_1.map
AnnotationLocal and focused refinement of mGlu2 CRD and 7TM domains
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Full-length mGlu2 in ago-PAM and L-Glutamate bound-state

EntireName: Full-length mGlu2 in ago-PAM and L-Glutamate bound-state
Components
  • Complex: Full-length mGlu2 in ago-PAM and L-Glutamate bound-state
    • Protein or peptide: Metabotropic glutamate receptor 2
  • Ligand: GLUTAMIC ACID
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 2-methoxy-6-propyl-N-(2-{4-[(1H-tetrazol-5-yl)methoxy]phenyl}ethyl)thieno[2,3-d]pyrimidin-4-amine

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Supramolecule #1: Full-length mGlu2 in ago-PAM and L-Glutamate bound-state

SupramoleculeName: Full-length mGlu2 in ago-PAM and L-Glutamate bound-state
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Metabotropic glutamate receptor 2 bound to ago-PAM ADX55164 and L-Glutamate
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 191 KDa

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Macromolecule #1: Metabotropic glutamate receptor 2

MacromoleculeName: Metabotropic glutamate receptor 2 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.932445 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: AEGPAKKVLT LEGDLVLGGL FPVHQKGGPA EDCGPVNEHR GIQRLEAMLF ALDRINRDPH LLPGVRLGAH ILDSCSKDTH ALEQALDFV RASLSRGADG SRHICPDGSY ATHGDAPTAI TGVIGGSYSD VSIQVANLLR LFQIPQISYA STSAKLSDKS R YDYFARTV ...String:
AEGPAKKVLT LEGDLVLGGL FPVHQKGGPA EDCGPVNEHR GIQRLEAMLF ALDRINRDPH LLPGVRLGAH ILDSCSKDTH ALEQALDFV RASLSRGADG SRHICPDGSY ATHGDAPTAI TGVIGGSYSD VSIQVANLLR LFQIPQISYA STSAKLSDKS R YDYFARTV PPDFFQAKAM AEILRFFNWT YVSTVASEGD YGETGIEAFE LEARARNICV ATSEKVGRAM SRAAFEGVVR AL LQKPSAR VAVLFTRSED ARELLAASQR LNASFTWVAS DGWGALESVV AGSEGAAEGA ITIELASYPI SDFASYFQSL DPW NNSRNP WFREFWEQRF RCSFRQRDCA AHSLRAVPFE QESKIMFVVN AVYAMAHALH NMHRALCPNT TRLCDAMRPV NGRR LYKDF VLNVKFDAPF RPADTHNEVR FDRFGDGIGR YNIFTYLRAG SGRYRYQKVG YWAEGLTLDT SLIPWASPSA GPLPA SRCS EPCLQNEVKS VQPGEVCCWL CIPCQPYEYR LDEFTCADCG LGYWPNASLT GCFELPQEYI RWGDAWAVGP VTIACL GAL ATLFVLGVFV RHNATPVVKA SGRELCYILL GGVFLCYCMT FIFIAKPSTA VCTLRRLGLG TAFSVCYSAL LTKTNRI AR IFGGAREGAQ RPRFISPASQ VAICLALISG QLLIVVAWLV VEAPGTGKET APERREVVTL RCNHRDASML GSLAYNVL L IALCTLYAFK TRKCPENFNE AKFIGFTMYT TCIIWLAFLP IFYVTSSDYR VQTTTMCVSV SLSGSVVLGC LFAPKLHII LFQPQKNVVS HRAPTSRFGS AAARASSSLG QGSGSQFVPT VCNGREVVDS TTSSL

UniProtKB: Metabotropic glutamate receptor 2

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Macromolecule #2: GLUTAMIC ACID

MacromoleculeName: GLUTAMIC ACID / type: ligand / ID: 2 / Number of copies: 2 / Formula: GLU
Molecular weightTheoretical: 147.129 Da
Chemical component information

ChemComp-GLU:
GLUTAMIC ACID

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #4: 2-methoxy-6-propyl-N-(2-{4-[(1H-tetrazol-5-yl)methoxy]phenyl}ethy...

MacromoleculeName: 2-methoxy-6-propyl-N-(2-{4-[(1H-tetrazol-5-yl)methoxy]phenyl}ethyl)thieno[2,3-d]pyrimidin-4-amine
type: ligand / ID: 4 / Number of copies: 1 / Formula: ZQY
Molecular weightTheoretical: 425.507 Da
Chemical component information

ChemComp-ZQY:
2-methoxy-6-propyl-N-(2-{4-[(1H-tetrazol-5-yl)methoxy]phenyl}ethyl)thieno[2,3-d]pyrimidin-4-amine

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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

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Support film - Material: GOLD / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.3 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2) / Number images used: 219019
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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