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- EMDB-47511: Human ASIC1a at pH 7.5 in complex with MitTx -

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Basic information

Entry
Database: EMDB / ID: EMD-47511
TitleHuman ASIC1a at pH 7.5 in complex with MitTx
Map dataMap of human ASIC1a at pH 7.5 in complex with MitTx
Sample
  • Complex: Homotrimeric complex of acid-sensing channel 1a with three bound MitTx heterodimers
    • Complex: Homotrimeric complex of human ASIC1a
      • Protein or peptide: Acid-sensing ion channel 1
    • Complex: Heterodimeric complex of MitTx alpha and beta subunits
      • Protein or peptide: Kunitz-type neurotoxin MitTx-alpha
      • Protein or peptide: Basic phospholipase A2 homolog MitTx-beta
KeywordsIon channel / Trimer / Toxin / MEMBRANE PROTEIN
Function / homology
Function and homology information


monoatomic ion-gated channel activity / : / sensory perception of sour taste / pH-gated monoatomic ion channel activity / cellular response to pH / ion channel regulator activity / arachidonate secretion / ligand-gated sodium channel activity / sodium ion transport / phospholipid metabolic process ...monoatomic ion-gated channel activity / : / sensory perception of sour taste / pH-gated monoatomic ion channel activity / cellular response to pH / ion channel regulator activity / arachidonate secretion / ligand-gated sodium channel activity / sodium ion transport / phospholipid metabolic process / regulation of postsynapse assembly / lipid catabolic process / sodium ion transmembrane transport / serine-type endopeptidase inhibitor activity / phospholipid binding / postsynaptic density membrane / Stimuli-sensing channels / calcium ion transport / toxin activity / calcium ion binding / dendrite / glutamatergic synapse / cell surface / extracellular region / plasma membrane
Similarity search - Function
Epithelial sodium channel, chordates / Epithelial sodium channel, conserved site / Amiloride-sensitive sodium channels signature. / Epithelial sodium channel / Amiloride-sensitive sodium channel / Phospholipase A2, aspartic acid active site / Phospholipase A2 aspartic acid active site. / Phospholipase A2 / Phospholipase A2 / Phospholipase A2 domain ...Epithelial sodium channel, chordates / Epithelial sodium channel, conserved site / Amiloride-sensitive sodium channels signature. / Epithelial sodium channel / Amiloride-sensitive sodium channel / Phospholipase A2, aspartic acid active site / Phospholipase A2 aspartic acid active site. / Phospholipase A2 / Phospholipase A2 / Phospholipase A2 domain / Phospholipase A2 / Phospholipase A2 domain superfamily / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily
Similarity search - Domain/homology
Kunitz-type neurotoxin MitTx-alpha / Basic phospholipase A2 homolog MitTx-beta / Acid-sensing ion channel 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Micrurus tener tener (cobra)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.33 Å
AuthorsHartfield KA / Yoshioka C / Cahill J / Baconguis I
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM138862 United States
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: Conformational plasticity of human acid-sensing ion channel 1a.
Authors: James Cahill / Kimberly A Hartfield / Stephanie Andrea Heusser / Nadine Ritter / Mette Homann Poulsen / Craig Yoshioka / Stephan Alexander Pless / Isabelle Baconguis /
Abstract: Acid-sensing ion channels (ASICs) are typically activated by acidic environments and contribute to nociception and synaptic plasticity. ASIC1a is the most abundant subunit in the central nervous ...Acid-sensing ion channels (ASICs) are typically activated by acidic environments and contribute to nociception and synaptic plasticity. ASIC1a is the most abundant subunit in the central nervous system and forms homomeric channels permeable to Na and Ca, making it a compelling therapeutic target for acidotic pathologies including stroke and traumatic brain injury. However, a complete conformational library of human ASIC1a has yet to be described. Here we show that human ASIC1a adopts six major conformations, resolved by cryo-electron microscopy across a pH range between 8.5 and 5.7 and in the presence of a toxin agonist and a gating-modifying amino acid substitution. These major conformations establish linear transmembrane helices to be associated with an open state, delineate mechanistic differences between proton and toxin activation and demonstrate that desensitization involves unexpected conformational diversity in the transmembrane domain. Together, they provide a three-dimensional framework to integrate previous structure-function studies on ASIC.
History
DepositionOct 24, 2024-
Header (metadata) releaseJan 21, 2026-
Map releaseJan 21, 2026-
UpdateJul 29, 2026-
Current statusJul 29, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47511.png

Downloads & links

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Map

FileDownload / File: emd_47511.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap of human ASIC1a at pH 7.5 in complex with MitTx
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.81 Å/pix.
x 360 pix.
= 293.04 Å		0.81 Å/pix.
x 360 pix.
= 293.04 Å		0.81 Å/pix.
x 360 pix.
= 293.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.814 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.0864819 - 0.2510672
Average (Standard dev.)0.0008320909 (±0.006388319)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 293.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_47511_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B corresponding to the primary map

Fileemd_47511_half_map_1.map
AnnotationHalf map B corresponding to the primary map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A corresponding to the primary map

Fileemd_47511_half_map_2.map
AnnotationHalf map A corresponding to the primary map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Homotrimeric complex of acid-sensing channel 1a with three bound ...

EntireName: Homotrimeric complex of acid-sensing channel 1a with three bound MitTx heterodimers
Components
  • Complex: Homotrimeric complex of acid-sensing channel 1a with three bound MitTx heterodimers
    • Complex: Homotrimeric complex of human ASIC1a
      • Protein or peptide: Acid-sensing ion channel 1
    • Complex: Heterodimeric complex of MitTx alpha and beta subunits
      • Protein or peptide: Kunitz-type neurotoxin MitTx-alpha
      • Protein or peptide: Basic phospholipase A2 homolog MitTx-beta

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Supramolecule #1: Homotrimeric complex of acid-sensing channel 1a with three bound ...

SupramoleculeName: Homotrimeric complex of acid-sensing channel 1a with three bound MitTx heterodimers
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: Homotrimeric complex of human ASIC1a

SupramoleculeName: Homotrimeric complex of human ASIC1a / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Heterodimeric complex of MitTx alpha and beta subunits

SupramoleculeName: Heterodimeric complex of MitTx alpha and beta subunits
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Micrurus tener tener (cobra)

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Macromolecule #1: Acid-sensing ion channel 1

MacromoleculeName: Acid-sensing ion channel 1 / type: protein_or_peptide / ID: 1
Details: Thrombin cleavage product of construct with N-terminal fusion of 8xHis-EGFP-Thrombin site
Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.252625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GGRMELKAEE EEVGGVQPVS IQAFASSSTL HGLAHIFSYE RLSLKRALWA LCFLGSLAVL LCVCTERVQY YFHYHHVTKL DEVAASQLT FPAVTLCNLN EFRFSQVSKN DLYHAGELLA LLNNRYEIPD TQMADEKQLE ILQDKANFRS FKPKPFNMRE F YDRAGHDI ...String:
GGRMELKAEE EEVGGVQPVS IQAFASSSTL HGLAHIFSYE RLSLKRALWA LCFLGSLAVL LCVCTERVQY YFHYHHVTKL DEVAASQLT FPAVTLCNLN EFRFSQVSKN DLYHAGELLA LLNNRYEIPD TQMADEKQLE ILQDKANFRS FKPKPFNMRE F YDRAGHDI RDMLLSCHFR GEVCSAEDFK VVFTRYGKCY TFNSGRDGRP RLKTMKGGTG NGLEIMLDIQ QDEYLPVWGE TD ETSFEAG IKVQIHSQDE PPFIDQLGFG VAPGFQTFVA CQEQRLIYLP PPWGTCKAVT MDSDLDFFDS YSITACRIDC ETR YLVENC NCRMVHMPGD APYCTPEQYK ECADPALDFL VEKDQEYCVC EMPCNLTRYG KELSMVKIPS KASAKYLAKK FNKS EQYIG ENILVLDIFF EVLNYETIEQ KKAYEIAGLL GDIGGQMGLF IGASILTVLE LFDYAYEVIK HKLCRRGKCQ KEAKR SSAD KGVALSLDDV KRHNPCESLR GHPAGMTYAA NILPHHPARG TFEDFTC

UniProtKB: Acid-sensing ion channel 1

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Macromolecule #2: Kunitz-type neurotoxin MitTx-alpha

MacromoleculeName: Kunitz-type neurotoxin MitTx-alpha / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Micrurus tener tener (cobra)
Molecular weightTheoretical: 7.117976 KDa
SequenceString:
(PCA)IRPAFCYED PPFFQKCGAF VDSYYFNRSR ITCVHFFYGQ CDVNQNHFTT MSECNRVCHG

UniProtKB: Kunitz-type neurotoxin MitTx-alpha

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Macromolecule #3: Basic phospholipase A2 homolog MitTx-beta

MacromoleculeName: Basic phospholipase A2 homolog MitTx-beta / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Micrurus tener tener (cobra)
Molecular weightTheoretical: 13.767645 KDa
SequenceString:
NLNQFRLMIK CTNDRVWADF VDYGCYCVAR DSNTPVDDLD RCCQAQKQCY DEAVKVHGCK PLVMFYSFEC RYLASDLDCS GNNTKCRNF VCNCDRTATL CILTATYNRN NHKIDPSRCQ

UniProtKB: Basic phospholipase A2 homolog MitTx-beta

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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

Concentration4 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
50.0 mMNa2HPO4/NaH2PO4sodium phosphate
200.0 mMNaClsodium chloride
1.0 mg/mLdigitonin
1.0 mMC9H15O6PTris(2-carboxyethyl)phosphine hydrochloride
GridModel: Quantifoil R2/1 / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 285.15 K / Instrument: FEI VITROBOT MARK IV
DetailsMonodisperse sample of homotrimeric ASIC1a mixed with MitTx alpha-beta complex

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / 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: 2.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.33 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 541317
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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