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- EMDB-6900: cASIC+Mambalgin1 -

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Basic information

Entry
Database: EMDB / ID: EMD-6900
TitlecASIC+Mambalgin1
Map data
Sample
  • Complex: cASIC and Mambalgin1
    • Complex: cASIC
      • Protein or peptide: cASIC
    • Complex: Mambalgin1
      • Protein or peptide: Mambalgin1
Biological speciesGallus gallus (chicken) / Dendroaspis polylepis polylepis (black mamba) / Gallus gallus
Methodsingle particle reconstruction / cryo EM / Resolution: 5.4 Å
AuthorsSun D / Yu Y / Xue X
CitationJournal: Cell Discov / Year: 2018
Title: Cryo-EM structure of the ASIC1a-mambalgin-1 complex reveals that the peptide toxin mambalgin-1 inhibits acid-sensing ion channels through an unusual allosteric effect.
Authors: Demeng Sun / You Yu / Xiaobin Xue / Man Pan / Ming Wen / Siyu Li / Qian Qu / Xiaorun Li / Longhua Zhang / Xueming Li / Lei Liu / Maojun Yang / Changlin Tian /
Abstract: Acid-sensing ion channels (ASICs) are neuronal voltage-independent Na channels that are activated by extracellular acidification. ASICs play essential roles in a wide range of physiological ...Acid-sensing ion channels (ASICs) are neuronal voltage-independent Na channels that are activated by extracellular acidification. ASICs play essential roles in a wide range of physiological processes, including sodium homeostasis, synaptic plasticity, neurodegeneration, and sensory transduction. Mambalgins, a family of three-finger toxins isolated from black mamba venom, specifically inhibit ASICs to exert strong analgesic effects in vivo, thus are thought to have potential therapeutic values against pain. However, the interaction and inhibition mechanism of mambalgin on ASICs remains elusive. Here, we report a cryo-electron microscopy (cryo-EM) structure of chicken ASIC1a (cASIC1a) in complex with mambalgin-1 toxin at 5.4 Å resolution. Our structure provides the first experimental evidence that mambalgin-1 interacts directly with the extracellular thumb domain of cASIC1a, rather than inserting into the acid-sensing pocket, as previously reported. Binding of mambalgin-1 leads to relocation of the thumb domain that could disrupt the acidic pocket of cASIC1a, illustrating an unusual inhibition mechanism of toxins on ASIC channels through an allosteric effect. These findings establish a structural basis for the toxicity of the mambalgins, and provide crucial insights for the development of new optimized inhibitors of ASICs.
History
DepositionJan 27, 2018-
Header (metadata) releaseJun 13, 2018-
Map releaseJun 13, 2018-
UpdateJun 20, 2018-
Current statusJun 20, 2018Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.132
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.132
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_6900.png

Downloads & links

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Map

FileDownload / File: emd_6900.map.gz / Format: CCP4 / Size: 2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 2.64 Å
Density
Contour LevelBy AUTHOR: 0.132 / Movie #1: 0.132
Minimum - Maximum-0.72954845 - 0.90948
Average (Standard dev.)0.00020159164 (±0.031357642)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions808080
Spacing808080
CellA=B=C: 211.20001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z2.642.642.64
M x/y/z808080
origin x/y/z0.0000.0000.000
length x/y/z211.200211.200211.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS808080
D min/max/mean-0.7300.9090.000

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Supplemental data

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Sample components

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Entire : cASIC and Mambalgin1

EntireName: cASIC and Mambalgin1
Components
  • Complex: cASIC and Mambalgin1
    • Complex: cASIC
      • Protein or peptide: cASIC
    • Complex: Mambalgin1
      • Protein or peptide: Mambalgin1

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Supramolecule #1: cASIC and Mambalgin1

SupramoleculeName: cASIC and Mambalgin1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Gallus gallus (chicken)

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Supramolecule #2: cASIC

SupramoleculeName: cASIC / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Dendroaspis polylepis polylepis (black mamba)

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Supramolecule #3: Mambalgin1

SupramoleculeName: Mambalgin1 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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Macromolecule #1: cASIC

MacromoleculeName: cASIC / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Gallus gallus
SequenceString: YPHVTKLDEV AATRLTFPAV TFCNLNEFRF SRVTKNDLYH AGELLALLNN RYEIPDTQTA DEKQLEILQD KANFRNFKPK PFNMLEFYDR AGHDIREMLL SCFFRGEQCS PEDFKVVFTR YGKCYTFNAG QDGKPRLITM KGGTGNGLEI MLDIQQDEYL PVWGETDETS ...String:
YPHVTKLDEV AATRLTFPAV TFCNLNEFRF SRVTKNDLYH AGELLALLNN RYEIPDTQTA DEKQLEILQD KANFRNFKPK PFNMLEFYDR AGHDIREMLL SCFFRGEQCS PEDFKVVFTR YGKCYTFNAG QDGKPRLITM KGGTGNGLEI MLDIQQDEYL PVWGETDETS FEAGIKVQIH SQDEPPLIDQ LGFGVAPGFQ TFVSCQEQRL IYLPPPWGDC KATTGDDTYS ITACRIDCET RYLVENCNCR MVHMPGDAPY CTPEQYKECA DPALDFLVEK DNEYCVCEMP CNVTRYGKEL SMVKIPSKAS AKYLAKKYNK SEQYIGENIL VLDIFFEALN YETIEQKK

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Macromolecule #2: Mambalgin1

MacromoleculeName: Mambalgin1 / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Dendroaspis polylepis polylepis (black mamba)
SequenceString:
LKCYQHGKVV TCHRDMKFCY HNTGMPFRNL KLILQGCSSS CSETENNKCC STDRCNK

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 55.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: RANDOM ASSIGNMENT
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 5.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 103000

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