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- PDB-9zpy: CNGA1 channel closed state in nanodisc with brain PIP2 cGMP-free -

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Basic information

Entry
Database: PDB / ID: 9zpy
TitleCNGA1 channel closed state in nanodisc with brain PIP2 cGMP-free
ComponentsCyclic nucleotide-gated channel alpha-1
KeywordsTRANSPORT PROTEIN / Cyclic nucleotide-gated channel / Rod photoreceptor / CNGA1 / Ion channel
Function / homology
Function and homology information


intracellular cyclic nucleotide activated cation channel complex / intracellularly cGMP-activated cation channel activity / intracellularly cAMP-activated cation channel activity / rod photoreceptor outer segment / photoreceptor outer segment membrane / sodium ion transport / sodium channel activity / monoatomic cation transmembrane transport / cGMP binding / cAMP binding ...intracellular cyclic nucleotide activated cation channel complex / intracellularly cGMP-activated cation channel activity / intracellularly cAMP-activated cation channel activity / rod photoreceptor outer segment / photoreceptor outer segment membrane / sodium ion transport / sodium channel activity / monoatomic cation transmembrane transport / cGMP binding / cAMP binding / visual perception / calcium channel activity / Activation of the phototransduction cascade / calcium ion transport / Inactivation, recovery and regulation of the phototransduction cascade / protein-containing complex binding / plasma membrane
Similarity search - Function
Cyclic nucleotide-gated channel, C-terminal leucine zipper domain / C-terminal leucine zipper domain of cyclic nucleotide-gated channels / : / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain ...Cyclic nucleotide-gated channel, C-terminal leucine zipper domain / C-terminal leucine zipper domain of cyclic nucleotide-gated channels / : / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain / Cyclic nucleotide-binding domain superfamily / RmlC-like jelly roll fold / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
CHOLESTEROL / : / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Chem-PT5 / Cyclic nucleotide-gated channel alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.48 Å
AuthorsPark, T. / Nimigean, C.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM124451 United States
CitationJournal: bioRxiv / Year: 2025
Title: PIP2 Binding at Allosteric Site Blocks Activation in Human Rod CNG Channels.
Authors: Taehyun Park / Crina M Nimigean /
Abstract: Phosphatidylinositol-4,5-bisphosphate (PIP2) is a ubiquitous signaling lipid that regulates multiple ion channels. In human cyclic nucleotide-gated (CNG) channels, including the rod photoreceptor ...Phosphatidylinositol-4,5-bisphosphate (PIP2) is a ubiquitous signaling lipid that regulates multiple ion channels. In human cyclic nucleotide-gated (CNG) channels, including the rod photoreceptor channel, PIP2 has been reported to exert inhibitory effects, but the underlying mechanism has remained unclear. Because this inhibition lowers the apparent cGMP sensitivity of rod CNG channels, it can play a key role in controlling the light sensitivity and dynamic range of rod photoreceptors. Here we report how PIP2 modulates the function of human CNGA1 channels, the major subunit of human rod photoreceptor CNG channels. Ensemble ion flux assays with liposome-reconstituted purified CNGA1 channels demonstrated robust inhibition by PIP2 via a reduction in apparent cGMP sensitivity, and single-channel recordings revealed PIP2 reduces the channel's open probability without altering unitary conductance. To uncover the structural basis, we determined cryo-EM structures of CNGA1 in lipid nanodiscs under multiple ligand conditions. In PIP2-free conditions, closed, intermediate, and open conformations were observed, whereas in the presence of PIP2, the open state was absent. Density consistent with bound PIP2 was detected at inter-protomer grooves between the voltage-sensing and pore domains indicating that PIP2 binding stabilizes non-conductive conformations by sterically preventing C-linker elevation and outward movement of helix S6, conformational changes needed for pore dilation. Collectively, our results establish a structural mechanism for PIP2-mediated inhibition of rod CNG channels, define a mechanistic framework for phosphoinositide control of ligand-gated channels across the CNG superfamily, and provide an inhibitory allosteric binding site for future drug targeting in this channel family.
History
DepositionDec 17, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 14, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 14, 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: Cyclic nucleotide-gated channel alpha-1
B: Cyclic nucleotide-gated channel alpha-1
C: Cyclic nucleotide-gated channel alpha-1
D: Cyclic nucleotide-gated channel alpha-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)283,95343
Polymers258,0774
Non-polymers25,87639
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
Cyclic nucleotide-gated channel alpha-1 / CNG channel alpha-1 / CNG-1 / CNG1 / Cyclic nucleotide-gated channel / photoreceptor / Rod ...CNG channel alpha-1 / CNG-1 / CNG1 / Cyclic nucleotide-gated channel / photoreceptor / Rod photoreceptor cGMP-gated cation channel subunit alpha / cGMP-gated cation channel alpha-1


Mass: 64519.238 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CNGA1, CNCG, CNCG1 / Cell line (production host): HEK293F / Production host: Homo sapiens (human) / References: UniProt: P29973
#2: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical...
ChemComp-PCW / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / (Z,Z)-4-HYDROXY-N,N,N-TRIMETHYL-10-OXO-7-[(1-OXO-9-OCTADECENYL)OXY]-3,5,9-TRIOXA-4-PHOSPHAHEPTACOS-18-EN-1-AMINIUM-4-OXIDE


Mass: 787.121 Da / Num. of mol.: 28 / Source method: obtained synthetically / Formula: C44H85NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: DOPC, phospholipid*YM
#4: Chemical
ChemComp-K / POTASSIUM ION


Mass: 39.098 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: K / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-PT5 / [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate / Phosphatidylinositol 4,5-bisphosphate / PtdIns(4,5)P2


Mass: 1047.088 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C47H85O19P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
Has ligand of interestY
Has protein modificationN

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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: homotetramer complex of Cyclic nucleotide-gated channel alpha-1
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.3165 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 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: 2600 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 48.56 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1crYOLOparticle selection
2PHENIX1.21_5207model refinement
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.48 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 195750 / Symmetry type: POINT
RefinementHighest resolution: 2.48 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00216367
ELECTRON MICROSCOPYf_angle_d0.40621979
ELECTRON MICROSCOPYf_dihedral_angle_d15.8173192
ELECTRON MICROSCOPYf_chiral_restr0.0372370
ELECTRON MICROSCOPYf_plane_restr0.0022635

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