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- PDB-9e4i: Human ASIC1a at pH 7.5 in complex with MitTx -

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Basic information

Entry
Database: PDB / ID: 9e4i
TitleHuman ASIC1a at pH 7.5 in complex with MitTx
Components
  • Acid-sensing ion channel 1
  • Basic phospholipase A2 homolog MitTx-beta
  • Kunitz-type neurotoxin MitTx-alpha
KeywordsMEMBRANE PROTEIN / Ion channel / Trimer / Toxin
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.33 Å
AuthorsHartfield, K.A. / Yoshioka, C. / Cahill, J. / Baconguis, I.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 21, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Acid-sensing ion channel 1
B: Acid-sensing ion channel 1
C: Acid-sensing ion channel 1
D: Kunitz-type neurotoxin MitTx-alpha
E: Basic phospholipase A2 homolog MitTx-beta
F: Kunitz-type neurotoxin MitTx-alpha
G: Basic phospholipase A2 homolog MitTx-beta
H: Kunitz-type neurotoxin MitTx-alpha
I: Basic phospholipase A2 homolog MitTx-beta


Theoretical massNumber of molelcules
Total (without water)243,4159
Polymers243,4159
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Acid-sensing ion channel 1 / ASIC1 / Amiloride-sensitive cation channel 2 / neuronal / Brain sodium channel 2 / BNaC2


Mass: 60252.625 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Details: Thrombin cleavage product of construct with N-terminal fusion of 8xHis-EGFP-Thrombin site
Source: (gene. exp.) Homo sapiens (human) / Gene: ASIC1, ACCN2, BNAC2 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: P78348
#2: Protein Kunitz-type neurotoxin MitTx-alpha


Mass: 7117.976 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Micrurus tener tener (cobra) / References: UniProt: G9I929
#3: Protein Basic phospholipase A2 homolog MitTx-beta / svPLA2 homolog


Mass: 13767.645 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Micrurus tener tener (cobra) / References: UniProt: G9I930
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

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

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Homotrimeric complex of acid-sensing channel 1a with three bound MitTx heterodimersCOMPLEXall0MULTIPLE SOURCES
2Homotrimeric complex of human ASIC1aCOMPLEX#11RECOMBINANT
3Heterodimeric complex of MitTx alpha and beta subunitsCOMPLEX#2-#31NATURAL
Molecular weight
IDEntity assembly-IDExperimental value
11NO
21NO
31NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Micrurus tener tener (cobra)1114302
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
21Homo sapiens (human)9606HEK293S GnTI-
32Homo sapiens (human)9606HEK293S GnTI-
43Homo sapiens (human)9606HEK293S GnTI-
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMsodium phosphateNa2HPO4/NaH2PO41
2200 mMsodium chlorideNaCl1
31 mg/mLdigitonin1
41 mMTris(2-carboxyethyl)phosphine hydrochlorideC9H15O6P1
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Monodisperse sample of homotrimeric ASIC1a mixed with MitTx alpha-beta complex
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 285.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2SerialEMimage acquisition
4cryoSPARCCTF correction
7Cootmodel fitting
8ISOLDEmodel fitting
10PHENIXmodel refinement
11cryoSPARCinitial Euler assignment
12cryoSPARCfinal Euler assignment
14cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.33 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 541317 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00214571
ELECTRON MICROSCOPYf_angle_d0.44219707
ELECTRON MICROSCOPYf_dihedral_angle_d4.531962
ELECTRON MICROSCOPYf_chiral_restr0.0372097
ELECTRON MICROSCOPYf_plane_restr0.0032589

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