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- PDB-9iqr: Cryo-EM structure of MT3-alpha2AAR -

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Basic information

Entry
Database: PDB / ID: 9iqr
TitleCryo-EM structure of MT3-alpha2AAR
Components
  • Alpha-2A adrenergic receptor,Soluble cytochrome b562
  • Muscarinic toxin 3
KeywordsMEMBRANE PROTEIN / complex
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 speciesDendroaspis angusticeps (eastern green mamba)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsZhong, Y.X. / Tao, H.H. / Tao, Y.Y.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 23, 2025Provider: repository / Type: Initial release
Revision 1.0Jul 23, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 23, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 23, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 23, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 23, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 23, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Feb 4, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Feb 4, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Muscarinic toxin 3
B: Alpha-2A adrenergic receptor,Soluble cytochrome b562


Theoretical massNumber of molelcules
Total (without water)56,2922
Polymers56,2922
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Muscarinic toxin 3 / MT3


Mass: 7396.488 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Dendroaspis angusticeps (eastern green mamba)
Production host: Homo sapiens (human) / References: UniProt: P81031
#2: Protein Alpha-2A adrenergic receptor,Soluble cytochrome b562 / Alpha-2 adrenergic receptor subtype C10 / Alpha-2A adrenoreceptor / Alpha-2A adrenoceptor / Alpha-2AAR


Mass: 48895.090 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) synthetic construct (others)
Gene: ADRA2A, ADRA2R, ADRAR / Production host: Homo sapiens (human) / References: UniProt: P08913
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: CELL / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: MT3-alpha2AAR complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Dendroaspis angusticeps (eastern green mamba)8618
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: NICKEL/TITANIUM / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: NITROGEN

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 5000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 52 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2264441 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0032692
ELECTRON MICROSCOPYf_angle_d0.5653664
ELECTRON MICROSCOPYf_dihedral_angle_d4.254353
ELECTRON MICROSCOPYf_chiral_restr0.045429
ELECTRON MICROSCOPYf_plane_restr0.005443

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