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- PDB-9let: Cryo-EM structure of human ZAC in zinc Binding State -

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Basic information

Entry
Database: PDB / ID: 9let
TitleCryo-EM structure of human ZAC in zinc Binding State
ComponentsLigand-gated cation channel ZACN,Genome polyprotein
KeywordsMEMBRANE PROTEIN / Cys-loop receptor / homopentamer / cation channel / zinc-binding state
Function / homology
Function and homology information


pH-gated monoatomic ion channel activity / transmembrane transporter complex / response to zinc ion / ligand-gated monoatomic cation channel activity / ligand-gated monoatomic ion channel activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / extracellular ligand-gated monoatomic ion channel activity / bioluminescence / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus ...pH-gated monoatomic ion channel activity / transmembrane transporter complex / response to zinc ion / ligand-gated monoatomic cation channel activity / ligand-gated monoatomic ion channel activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / extracellular ligand-gated monoatomic ion channel activity / bioluminescence / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / generation of precursor metabolites and energy / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / ribonucleoside triphosphate phosphatase activity / transmembrane signaling receptor activity / nucleoside-triphosphate phosphatase / channel activity / monoatomic ion transmembrane transport / DNA replication / RNA helicase activity / endocytosis involved in viral entry into host cell / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / virion attachment to host cell / host cell nucleus / structural molecule activity / proteolysis / RNA binding / zinc ion binding / ATP binding / plasma membrane
Similarity search - Function
Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / : / Green fluorescent protein, GFP / Picornavirus coat protein / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily ...Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / : / Green fluorescent protein, GFP / Picornavirus coat protein / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily / Neurotransmitter-gated ion-channel ligand binding domain / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Picornavirus capsid / picornavirus capsid protein / Helicase, superfamily 3, single-stranded RNA virus / Superfamily 3 helicase of positive ssRNA viruses domain profile. / Helicase, superfamily 3, single-stranded DNA/RNA virus / RNA helicase / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Ligand-gated cation channel ZACN
Similarity search - Component
Biological speciesHomo sapiens (human)
Enterovirus A71
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.62 Å
AuthorsQu, Q. / Zhou, Z.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371256 China
National Natural Science Foundation of China (NSFC)32171194 China
National Natural Science Foundation of China (NSFC)32401007 China
CitationJournal: Cell Discov / Year: 2026
Title: Structural basis of human zinc-activated channel (ZAC) signaling and modulation.
Authors: Zixuan Zhou / Yonghui Long / Yulin Chao / Chuanhui Yang / Yi-Quan Tang / Yilai Shu / Hongtao Zhu / Anders A Jensen / Qianhui Qu /
Abstract: Zinc (Zn) plays essential roles in a plethora of physiological processes, including key functions as a neuromodulator. The zinc-activated channel (ZAC) belongs to the Cys-loop receptor (CLR) ...Zinc (Zn) plays essential roles in a plethora of physiological processes, including key functions as a neuromodulator. The zinc-activated channel (ZAC) belongs to the Cys-loop receptor (CLR) superfamily of pentameric ligand-gated ion channels, which also comprises receptors for the important neurotransmitters acetylcholine, serotonin, GABA and glycine. In contrast to these classical CLRs, which have been extensively explored over decades, ZAC remains poorly characterized despite its potential significance in mammals. Here, we present several cryo-EM structures of human ZAC, including the ligand-free resting state, the Zn-bound state, and several antagonist-bound states. In the Zn-bound structure, Zn ions bind to the subunit interfaces of the extracellular domain, corresponding to the canonical agonist-binding sites in the classical CLRs, and are primarily coordinated through cation‒π interactions with two aromatic residues. While the antagonist TTFB inhibits ZAC by insertion between the transmembrane M2 helices of adjacent subunits, d-tubocurarine acts in a dual manner by blocking the channel and interfering with agonist binding. Combined with mutagenesis and electrophysiological analysis, these evaluations highlight the distinctive structural and functional features of this atypical CLR.
History
DepositionJan 7, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 22, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 22, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ligand-gated cation channel ZACN,Genome polyprotein
B: Ligand-gated cation channel ZACN,Genome polyprotein
E: Ligand-gated cation channel ZACN,Genome polyprotein
D: Ligand-gated cation channel ZACN,Genome polyprotein
C: Ligand-gated cation channel ZACN,Genome polyprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)400,34720
Polymers394,1545
Non-polymers6,19215
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
Ligand-gated cation channel ZACN,Genome polyprotein / Ligand-gated ion channel zinc-activated 1 / Ligand-gated ion-channel receptor L2 / Zinc-activated channel


Mass: 78830.859 Da / Num. of mol.: 5 / Mutation: A152T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Enterovirus A71
Gene: ZACN, L2, LGICZ, LGICZ1, ZAC / Cell line (production host): HEK293F / Production host: Homo sapiens (human)
References: UniProt: Q401N2, UniProt: B6F2F5, picornain 2A, nucleoside-triphosphate phosphatase, picornain 3C, RNA-directed RNA polymerase
#2: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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

ComponentName: ZAC in complex with zinc ion / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
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: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 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: 2000 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
9PHENIX1.19.2_4158model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.62 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 164569 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL

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