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- EMDB-60793: Cryo-EM structure of MT3-alpha2AAR -

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Basic information

Entry
Database: EMDB / ID: EMD-60793
TitleCryo-EM structure of MT3-alpha2AAR
Map data
Sample
  • Complex: MT3-alpha2AAR complex
    • Protein or peptide: Muscarinic toxin 3
    • Protein or peptide: Alpha-2A adrenergic receptor,Soluble cytochrome b562
Keywordscomplex / MEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of uterine smooth muscle contraction / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / alpha-2C adrenergic receptor binding / epinephrine binding / phospholipase C-activating adrenergic receptor signaling pathway / alpha-1B adrenergic receptor binding / negative regulation of norepinephrine secretion / negative regulation of epinephrine secretion ...negative regulation of uterine smooth muscle contraction / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / alpha-2C adrenergic receptor binding / epinephrine binding / phospholipase C-activating adrenergic receptor signaling pathway / alpha-1B adrenergic receptor binding / negative regulation of norepinephrine secretion / negative regulation of epinephrine secretion / heterotrimeric G-protein binding / negative regulation of calcium ion-dependent exocytosis / Surfactant metabolism / positive regulation of potassium ion transport / dopaminergic synapse / thermoception / fear response / thioesterase binding / negative regulation of insulin secretion involved in cellular response to glucose stimulus / norepinephrine binding / positive regulation of membrane protein ectodomain proteolysis / Adrenoceptors / response to alcohol / intestinal absorption / adrenergic receptor signaling pathway / positive regulation of wound healing / response to morphine / negative regulation of calcium ion transport / negative regulation of lipid catabolic process / regulation of vasoconstriction / positive regulation of epidermal growth factor receptor signaling pathway / cellular response to hormone stimulus / Rho protein signal transduction / adenylate cyclase-activating adrenergic receptor signaling pathway / presynaptic active zone membrane / presynaptic modulation of chemical synaptic transmission / axon terminus / guanyl-nucleotide exchange factor activity / positive regulation of cytokine production / female pregnancy / negative regulation of insulin secretion / platelet activation / postsynaptic density membrane / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / GABA-ergic synapse / vasodilation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (z) signalling events / glucose homeostasis / toxin activity / actin cytoskeleton organization / G alpha (i) signalling events / basolateral plasma membrane / Ras protein signal transduction / DNA replication / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / positive regulation of MAPK cascade / positive regulation of cell migration / G protein-coupled receptor signaling pathway / protein heterodimerization activity / neuronal cell body / positive regulation of cell population proliferation / protein kinase binding / glutamatergic synapse / protein homodimerization activity / extracellular region / plasma membrane / cytoplasm
Similarity search - Function
Alpha 2A adrenoceptor / Snake cytotoxin, cobra-type / Snake toxin, conserved site / Snake toxins signature. / : / Snake toxin cobra-type / Snake three-finger toxin / Adrenoceptor family / Snake toxin-like superfamily / Serpentine type 7TM GPCR chemoreceptor Srsx ...Alpha 2A adrenoceptor / Snake cytotoxin, cobra-type / Snake toxin, conserved site / Snake toxins signature. / : / Snake toxin cobra-type / Snake three-finger toxin / Adrenoceptor family / Snake toxin-like superfamily / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
Alpha-2A adrenergic receptor / Muscarinic toxin 3
Similarity search - Component
Biological speciesHomo sapiens (human) / Dendroaspis angusticeps (eastern green mamba)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsZhong YX / Tao HH / Tao YY
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2025
Title: Structure-guided engineering of snake toxins for selective modulation of adrenergic and muscarinic receptors.
Authors: Yixuan Zhong / Huihui Tao / Yu Zhang / Binbin He / Haizhan Jiao / Dandan Wang / Maikun Teng / Hongli Hu / Qiong Guo / Yuyong Tao /
Abstract: Adrenergic receptors (ARs) and muscarinic acetylcholine receptors (mAChRs) are essential G protein-coupled receptors (GPCRs) that regulate a wide range of physiological processes. Despite their ...Adrenergic receptors (ARs) and muscarinic acetylcholine receptors (mAChRs) are essential G protein-coupled receptors (GPCRs) that regulate a wide range of physiological processes. Despite their significance, developing subtype-selective modulators for these receptors has been a formidable challenge due to the high structural and sequence similarities within their subfamilies. In this study, we elucidated the recognition and regulatory mechanisms of ARs and mAChRs by muscarinic toxin 3 (MT3), a cross-reactive ligand derived from snake venom. By leveraging the distinct toxin-receptor interfaces, we engineer a panel of toxin variants capable of selectively modulating α2A and MAChR using computational design and directed evolution. These subtype-selective toxins not only provide valuable tools for basic research but also hold therapeutic potential for diseases associated with these GPCRs. This study further underscores the effectiveness of structure-guided approaches in transforming venom-derived scaffolds into receptor-specific modulators.
History
DepositionJul 13, 2024-
Header (metadata) releaseJul 23, 2025-
Map releaseJul 23, 2025-
UpdateFeb 4, 2026-
Current statusFeb 4, 2026Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_60793.png

Downloads & links

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Map

FileDownload / File: emd_60793.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 280 pix.
= 299.6 Å		1.07 Å/pix.
x 280 pix.
= 299.6 Å		1.07 Å/pix.
x 280 pix.
= 299.6 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.469
Minimum - Maximum-2.6503181 - 3.5812097
Average (Standard dev.)-0.0011280227 (±0.061502725)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 299.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_60793_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_60793_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : MT3-alpha2AAR complex

EntireName: MT3-alpha2AAR complex
Components
  • Complex: MT3-alpha2AAR complex
    • Protein or peptide: Muscarinic toxin 3
    • Protein or peptide: Alpha-2A adrenergic receptor,Soluble cytochrome b562

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Supramolecule #1: MT3-alpha2AAR complex

SupramoleculeName: MT3-alpha2AAR complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Muscarinic toxin 3

MacromoleculeName: Muscarinic toxin 3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Dendroaspis angusticeps (eastern green mamba)
Molecular weightTheoretical: 7.396488 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
LTCVTKNTIF GITTENCPAG QNLCFKRWHY VIPRYTEITR GCAATCPIPE NYDSIHCCKT DKCNE

UniProtKB: Muscarinic toxin 3

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Macromolecule #2: Alpha-2A adrenergic receptor,Soluble cytochrome b562

MacromoleculeName: Alpha-2A adrenergic receptor,Soluble cytochrome b562 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 48.89509 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ARATPYSLQV TLTLVCLAGL LMLLTVFGNV LVIIAVFTSR ALKAPQNLFL VSLASADILV ATLVIPFSLA NEVMGYWYFG KAWCEIYLA LDVLFCTSSI VHLCAISLDR YWSITQAIEY NLKRTPRRIK AIIITVWVIS AVISFPPLIS IEKKGGGGGP Q PAEPRCEI ...String:
ARATPYSLQV TLTLVCLAGL LMLLTVFGNV LVIIAVFTSR ALKAPQNLFL VSLASADILV ATLVIPFSLA NEVMGYWYFG KAWCEIYLA LDVLFCTSSI VHLCAISLDR YWSITQAIEY NLKRTPRRIK AIIITVWVIS AVISFPPLIS IEKKGGGGGP Q PAEPRCEI NDQKWYVISS CIGSFFAPCL IMILVYVRIY QIAKRRAADL EDNWETLNDN LKVIEKADNA AQVKDALTKM RA AALDAQK ASGSGSPEMK DFRHGFDILV GQIDDALKLA NEGKVKEAQA AAEQLKTTRN AYIQKYLAGR QNREKRFTFV LAV VIGVFV VCWFPFFFTY TLTAVGCSVP RTLFKFFFWF GYCNSSLNPV IYTIFNHDFR RAFKKILKIA ALKEKIAALK EKIA ALKEA EEKRASRLEE ELRRRLTEGS HHHHHHHH

UniProtKB: Alpha-2A adrenergic receptor, Alpha-2A adrenergic receptor

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: NICKEL/TITANIUM / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: NITROGEN / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2264441
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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