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- EMDB-74540: CNGA1 channel intermediate state in nanodisc with diC8-PIP2 cGMP-bound -

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Basic information

Entry
Database: EMDB / ID: EMD-74540
TitleCNGA1 channel intermediate state in nanodisc with diC8-PIP2 cGMP-bound
Map data
Sample
  • Complex: homotetramer complex of Cyclic nucleotide-gated channel alpha-1
    • Protein or peptide: Cyclic nucleotide-gated channel alpha-1
  • Ligand: CYCLIC GUANOSINE MONOPHOSPHATE
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
  • Ligand: POTASSIUM ION
KeywordsCyclic nucleotide-gated channel / Rod photoreceptor / CNGA1 / Ion channel / TRANSPORT PROTEIN
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
Cyclic nucleotide-gated channel alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.22 Å
AuthorsPark T / Nimigean CM
Funding support United States, 1 items
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, 2025-
Header (metadata) releaseJan 14, 2026-
Map releaseJan 14, 2026-
UpdateJan 14, 2026-
Current statusJan 14, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_74540.png

Downloads & links

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Map

FileDownload / File: emd_74540.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.9 Å/pix.
x 352 pix.
= 316.8 Å		0.9 Å/pix.
x 352 pix.
= 316.8 Å		0.9 Å/pix.
x 352 pix.
= 316.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0054
Minimum - Maximum-0.012055347 - 0.040275432
Average (Standard dev.)-0.0000048046068 (±0.0010432535)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 316.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_74540_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_74540_half_map_2.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 : homotetramer complex of Cyclic nucleotide-gated channel alpha-1

EntireName: homotetramer complex of Cyclic nucleotide-gated channel alpha-1
Components
  • Complex: homotetramer complex of Cyclic nucleotide-gated channel alpha-1
    • Protein or peptide: Cyclic nucleotide-gated channel alpha-1
  • Ligand: CYCLIC GUANOSINE MONOPHOSPHATE
  • Ligand: CHOLESTEROL
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
  • Ligand: POTASSIUM ION

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Supramolecule #1: homotetramer complex of Cyclic nucleotide-gated channel alpha-1

SupramoleculeName: homotetramer complex of Cyclic nucleotide-gated channel alpha-1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 316.5 KDa

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Macromolecule #1: Cyclic nucleotide-gated channel alpha-1

MacromoleculeName: Cyclic nucleotide-gated channel alpha-1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 64.519238 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDKGG SASKDKKEEE KKEVVVIDPS GNTYYNWLFC ITLPVMYNWT MVIARACFDE LQSDYLEYWL ILDYVSDIVY LIDMFVRTR TGYLEQGLLV KEELKLINKY KSNLQFKLDV LSLIPTDLLY FKLGWNYPEI RLNRLLRFSR MFEFFQRTET R TNYPNIFR ...String:
DYKDDDDKGG SASKDKKEEE KKEVVVIDPS GNTYYNWLFC ITLPVMYNWT MVIARACFDE LQSDYLEYWL ILDYVSDIVY LIDMFVRTR TGYLEQGLLV KEELKLINKY KSNLQFKLDV LSLIPTDLLY FKLGWNYPEI RLNRLLRFSR MFEFFQRTET R TNYPNIFR ISNLVMYIVI IIHWNACVFY SISKAIGFGN DTWVYPDIND PEFGRLARKY VYSLYWSTLT LTTIGETPPP VR DSEYVFV VVDFLIGVLI FATIVGNIGS MISNMNAARA EFQARIDAIK QYMHFRNVSK DMEKRVIKWF DYLWTNKKTV DEK EVLKYL PDKLRAEIAI NVHLDTLKKV RIFADCEAGL LVELVLKLQP QVYSPGDYIC KKGDIGREMY IIKEGKLAVV ADDG VTQFV VLSDGSYFGE ISILNIKGSK AGNRRTANIK SIGYSDLFCL SKDDLMEALT EYPDAKTMLE EKGKQILMKD GLLDL NIAN AGSDPKDLEE KVTRMEGSVD LLQTRFARIL AEYESMQQKL KQRLTKVEKF LKPLIDTEFS SIEGPGAESG PIDST

UniProtKB: Cyclic nucleotide-gated channel alpha-1

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Macromolecule #2: CYCLIC GUANOSINE MONOPHOSPHATE

MacromoleculeName: CYCLIC GUANOSINE MONOPHOSPHATE / type: ligand / ID: 2 / Number of copies: 4 / Formula: PCG
Molecular weightTheoretical: 345.205 Da
Chemical component information

ChemComp-PCG:
CYCLIC GUANOSINE MONOPHOSPHATE

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #4: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 4 / Number of copies: 28 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

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Macromolecule #5: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(o...

MacromoleculeName: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate
type: ligand / ID: 5 / Number of copies: 4 / Formula: PIO
Molecular weightTheoretical: 746.566 Da
Chemical component information

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

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Macromolecule #6: POTASSIUM ION

MacromoleculeName: POTASSIUM ION / type: ligand / ID: 6 / Number of copies: 5 / Formula: K
Molecular weightTheoretical: 39.098 Da

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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: 7.4
Component:
ConcentrationNameFormula
25.0 mMHEPES
150.0 mMpotassiumKCl

Details: 25 mM HEPES, 150 mM KCl, pH 7.4
GridModel: Quantifoil R1.2/1.3 / Material: GOLD
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 48.48 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.6 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.22 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 332474
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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