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- EMDB-36090: Structure of Muscarinic receptor (M2R) in complex with beta-arres... -

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Entry
Database: EMDB / ID: EMD-36090
TitleStructure of Muscarinic receptor (M2R) in complex with beta-arrestin1 (Local refine, cross-linked)
Map data
Sample
  • Complex: Muscarinic receptor (M2R) in complex with beta-arrestin1
    • Complex: beta-arrestin1
      • Protein or peptide: Beta-arrestin-1
    • Complex: Fab30
      • Protein or peptide: Fab30 Heavy Chain
      • Protein or peptide: Fab30 Light Chain
    • Complex: Muscarinic receptor M2R
      • Protein or peptide: Muscarinic acetylcholine receptor M2
KeywordsGPCR / Arrestin / SIGNALING PROTEIN / SIGNALING PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


TGFBR3 regulates TGF-beta signaling / MAP2K and MAPK activation / Activation of SMO / Golgi Associated Vesicle Biogenesis / Lysosome Vesicle Biogenesis / Muscarinic acetylcholine receptors / G protein-coupled acetylcholine receptor activity / AP-2 adaptor complex binding / phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway / Ub-specific processing proteases ...TGFBR3 regulates TGF-beta signaling / MAP2K and MAPK activation / Activation of SMO / Golgi Associated Vesicle Biogenesis / Lysosome Vesicle Biogenesis / Muscarinic acetylcholine receptors / G protein-coupled acetylcholine receptor activity / AP-2 adaptor complex binding / phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway / Ub-specific processing proteases / clathrin coat of coated pit / clathrin heavy chain binding / cholinergic synapse / Cargo recognition for clathrin-mediated endocytosis / desensitization of G protein-coupled receptor signaling pathway / regulation of smooth muscle contraction / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / Clathrin-mediated endocytosis / clathrin-dependent endocytosis / acetylcholine receptor binding / G protein-coupled receptor internalization / arrestin family protein binding / inositol hexakisphosphate binding / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (s) signalling events / clathrin binding / small molecule binding / regulation of heart contraction / pseudopodium / phosphatidylinositol-3,4,5-trisphosphate binding / positive regulation of receptor internalization / negative regulation of Notch signaling pathway / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / presynaptic modulation of chemical synaptic transmission / clathrin-coated endocytic vesicle membrane / G protein-coupled receptor binding / receptor internalization / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to virus / positive regulation of protein phosphorylation / G protein-coupled acetylcholine receptor signaling pathway / Cargo recognition for clathrin-mediated endocytosis / nervous system development / protein transport / presynapse / Clathrin-mediated endocytosis / cytoplasmic vesicle / ubiquitin-dependent protein catabolic process / G alpha (i) signalling events / chemical synaptic transmission / molecular adaptor activity / postsynaptic membrane / positive regulation of ERK1 and ERK2 cascade / cilium / ciliary basal body / G protein-coupled receptor signaling pathway / synapse / dendrite / nucleolus / Golgi apparatus / signal transduction / nucleus / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Muscarinic acetylcholine receptor M2 / Muscarinic acetylcholine receptor family / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain ...Muscarinic acetylcholine receptor M2 / Muscarinic acetylcholine receptor family / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin-like, C-terminal / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / Immunoglobulin E-set
Similarity search - Domain/homology
Muscarinic acetylcholine receptor M2 / Beta-arrestin-1
Similarity search - Component
Biological speciesBos taurus (domestic cattle) / Mus musculus (house mouse) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsMaharana J / Sano FK / Shihoya W / Banerjee R / Nureki O / Shukla AK
Funding support India, 4 items
OrganizationGrant numberCountry
Science and Engineering Research Board (SERB)IPA/2020/000405 India
Department of Biotechnology (DBT, India)IA/S/20/1/504916 India
Science and Engineering Research Board (SERB)CRG/2022/002646 India
Science and Engineering Research Board (SERB)SPR/2020/000408 India
CitationJournal: Science / Year: 2024
Title: Molecular insights into atypical modes of β-arrestin interaction with seven transmembrane receptors.
Authors: Jagannath Maharana / Fumiya K Sano / Parishmita Sarma / Manish K Yadav / Longhan Duan / Tomasz M Stepniewski / Madhu Chaturvedi / Ashutosh Ranjan / Vinay Singh / Sayantan Saha / Gargi ...Authors: Jagannath Maharana / Fumiya K Sano / Parishmita Sarma / Manish K Yadav / Longhan Duan / Tomasz M Stepniewski / Madhu Chaturvedi / Ashutosh Ranjan / Vinay Singh / Sayantan Saha / Gargi Mahajan / Mohamed Chami / Wataru Shihoya / Jana Selent / Ka Young Chung / Ramanuj Banerjee / Osamu Nureki / Arun K Shukla /
Abstract: β-arrestins (βarrs) are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor ...β-arrestins (βarrs) are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor activation and phosphorylation. Here, we present seven cryo-electron microscopy structures of βarrs either in the basal state, activated by the muscarinic receptor subtype 2 (M2R) through its third intracellular loop, or activated by the βarr-biased decoy D6 receptor (D6R). Combined with biochemical, cellular, and biophysical experiments, these structural snapshots allow the visualization of atypical engagement of βarrs with 7TMRs and also reveal a structural transition in the carboxyl terminus of βarr2 from a β strand to an α helix upon activation by D6R. Our study provides previously unanticipated molecular insights into the structural and functional diversity encoded in 7TMR-βarr complexes with direct implications for exploring novel therapeutic avenues.
History
DepositionMay 2, 2023-
Header (metadata) releaseDec 27, 2023-
Map releaseDec 27, 2023-
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36090.png

Downloads & links

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Map

FileDownload / File: emd_36090.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.35 Å/pix.
x 256 pix.
= 345.267 Å		1.35 Å/pix.
x 256 pix.
= 345.267 Å		1.35 Å/pix.
x 256 pix.
= 345.267 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.3487 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.014
Minimum - Maximum-0.018238664 - 1.9364787
Average (Standard dev.)0.0003337101 (±0.011066436)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 345.2672 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36090_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36090_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Muscarinic receptor (M2R) in complex with beta-arrestin1

EntireName: Muscarinic receptor (M2R) in complex with beta-arrestin1
Components
  • Complex: Muscarinic receptor (M2R) in complex with beta-arrestin1
    • Complex: beta-arrestin1
      • Protein or peptide: Beta-arrestin-1
    • Complex: Fab30
      • Protein or peptide: Fab30 Heavy Chain
      • Protein or peptide: Fab30 Light Chain
    • Complex: Muscarinic receptor M2R
      • Protein or peptide: Muscarinic acetylcholine receptor M2

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Supramolecule #1: Muscarinic receptor (M2R) in complex with beta-arrestin1

SupramoleculeName: Muscarinic receptor (M2R) in complex with beta-arrestin1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: beta-arrestin1

SupramoleculeName: beta-arrestin1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Bos taurus (domestic cattle)

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Supramolecule #3: Fab30

SupramoleculeName: Fab30 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Mus musculus (house mouse)

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Supramolecule #4: Muscarinic receptor M2R

SupramoleculeName: Muscarinic receptor M2R / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Beta-arrestin-1

MacromoleculeName: Beta-arrestin-1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 39.656668 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GTRVFKKASP NGKLTVYLGK RDFVDHIDLV EPVDGVVLVD PEYLKERRVY VTLTCAFRYG REDLDVLGLT FRKDLFVANV QSFPPAPED KKPLTRLQER LIKKLGEHAY PFTFEIPPNL PCSVTLQPGP EDTGKACGVD YEVKAFCAEN LEEKIHKRNS V RLVIRKVQ ...String:
GTRVFKKASP NGKLTVYLGK RDFVDHIDLV EPVDGVVLVD PEYLKERRVY VTLTCAFRYG REDLDVLGLT FRKDLFVANV QSFPPAPED KKPLTRLQER LIKKLGEHAY PFTFEIPPNL PCSVTLQPGP EDTGKACGVD YEVKAFCAEN LEEKIHKRNS V RLVIRKVQ YAPERPGPQP TAETTRQFLM SDKPLHLEAS LDKEIYYHGE PISVNVHVTN NTNKTVKKIK ISVRQYADIC LF NTAQYKC PVAMEEADDT VAPSSTFCKV YTLTPFLANN REKRGLALDG KLKHEDTNLA SSTLLREGAN REILGIIVSY KVK VKLVVS RGGLLGDLAS SDVAVELPFT LMHPKPK

UniProtKB: Beta-arrestin-1

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Macromolecule #2: Fab30 Heavy Chain

MacromoleculeName: Fab30 Heavy Chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 12.861245 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
VQLVESGGGL VQPGGSLRLS CAASGFNVYS SSIHWVRQAP GKGLEWVASI SSYYGYTYYA DSVKGRFTIS ADTSKNTAYL QMNSLRAED TAVYYCARSR QFWYSGLDYW GQGTLVTV

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Macromolecule #3: Fab30 Light Chain

MacromoleculeName: Fab30 Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 11.50082 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QYKYVPVTFG QGTKVEI

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Macromolecule #4: Muscarinic acetylcholine receptor M2

MacromoleculeName: Muscarinic acetylcholine receptor M2 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.226853 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
EN(TPO)V(SEP)(TPO)(SEP)LG

UniProtKB: Muscarinic acetylcholine receptor M2

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Number real images: 17869 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 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

Particle selectionNumber selected: 5235492
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8go8

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.0) / Number images used: 63372
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationSoftware - Name: cryoSPARC (ver. 3.3.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8go8


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8j97:
Structure of Muscarinic receptor (M2R) in complex with beta-arrestin1 (Local refine, cross-linked)

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