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- PDB-7n17: Structure of TAX-4_R421W apo open state -

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Basic information

Entry
Database: PDB / ID: 7n17
TitleStructure of TAX-4_R421W apo open state
ComponentsCyclic nucleotide-gated cation channel
KeywordsTRANSPORT PROTEIN / ion channel / blindness-associated mutation / achromatopsia / phototransduction
Function / homology
Function and homology information


detection of carbon dioxide / detection of chemical stimulus involved in sensory perception / ciliary inversin compartment / Activation of the phototransduction cascade / Inactivation, recovery and regulation of the phototransduction cascade / VxPx cargo-targeting to cilium / thermosensory behavior / positive regulation of growth rate / intracellular cyclic nucleotide activated cation channel complex / olfactory behavior ...detection of carbon dioxide / detection of chemical stimulus involved in sensory perception / ciliary inversin compartment / Activation of the phototransduction cascade / Inactivation, recovery and regulation of the phototransduction cascade / VxPx cargo-targeting to cilium / thermosensory behavior / positive regulation of growth rate / intracellular cyclic nucleotide activated cation channel complex / olfactory behavior / intracellularly cGMP-activated cation channel activity / chemosensory behavior / aerotaxis / intracellularly cAMP-activated cation channel activity / G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger / response to oxygen levels / cation channel complex / thermotaxis / multicellular organismal reproductive process / non-motile cilium / regulation of axon extension / regulation of neuron differentiation / negative regulation of cGMP-mediated signaling / voltage-gated potassium channel activity / monoatomic cation transmembrane transport / phototransduction / cGMP binding / response to hyperoxia / neuron projection morphogenesis / calcium-mediated signaling / chemotaxis / dendrite / protein-containing complex binding / positive regulation of gene expression / positive regulation of transcription by RNA polymerase II / membrane / identical protein 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 / Potassium channel, voltage-dependent, EAG/ELK/ERG / 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 / Potassium channel, voltage-dependent, EAG/ELK/ERG / 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
Chem-CPL / Cyclic nucleotide-gated cation channel
Similarity search - Component
Biological speciesCaenorhabditis elegans (invertebrata)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsZheng, X. / Li, H. / Hu, Z. / Su, D. / Yang, J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Eye Institute (NIH/NEI)R01EY027800 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM085234 United States
CitationJournal: Commun Biol / Year: 2022
Title: Structural and functional characterization of an achromatopsia-associated mutation in a phototransduction channel.
Authors: Xiangdong Zheng / Huan Li / Zhengshan Hu / Deyuan Su / Jian Yang /
Abstract: Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often unclear. We investigated the ...Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often unclear. We investigated the structural basis and molecular/cellular effects of R410W, an achromatopsia-associated, presumed loss-of-function mutation in human CNGA3. Cryo-EM structures of the Caenorhabditis elegans TAX-4 CNG channel carrying the analogous mutation, R421W, show that most apo channels are open. R421, located in the gating ring, interacts with the S4 segment in the closed state. R421W disrupts this interaction, destabilizes the closed state, and stabilizes the open state. CNGA3_R410W/CNGB3 and TAX4_R421W channels are spontaneously active without cGMP and induce cell death, suggesting cone degeneration triggered by spontaneous CNG channel activity as a possible cause of achromatopsia. Our study sheds new light on CNG channel allosteric gating, provides an impetus for a reevaluation of reported loss-of-function CNG channel missense disease mutations, and has implications for mutation-specific treatment of retinopathy.
History
DepositionMay 27, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 16, 2022Provider: repository / Type: Initial release

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Assembly

Deposited unit
A: Cyclic nucleotide-gated cation channel
B: Cyclic nucleotide-gated cation channel
C: Cyclic nucleotide-gated cation channel
D: Cyclic nucleotide-gated cation channel
hetero molecules


Theoretical massNumber of molelcules
Total (without water)355,53328
Polymers337,3404
Non-polymers18,19324
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area36810 Å2
ΔGint-214 kcal/mol
Surface area98260 Å2

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Components

#1: Protein
Cyclic nucleotide-gated cation channel / Abnormal chemotaxis protein 4


Mass: 84334.914 Da / Num. of mol.: 4 / Mutation: R421W
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Caenorhabditis elegans (invertebrata) / Gene: tax-4, ZC84.2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q03611
#2: Chemical...
ChemComp-CPL / 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / PALMITOYL-LINOLEOYL PHOSPHATIDYLCHOLINE / Phosphatidylcholine


Mass: 758.060 Da / Num. of mol.: 24 / Source method: obtained synthetically / Formula: C42H80NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
Has ligand of interestY

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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: Cyclic nucleotide-gated channel TAX-4 with R421W mutation
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Caenorhabditis elegans (invertebrata)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: OTHER
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.15.2_3472: / Classification: refinement
EM software
IDNameVersionCategory
1RELIONparticle selection
2Leginonimage acquisition
4GctfCTF correction
7Cootmodel fitting
8PHENIXmodel fitting
10PHENIXmodel refinement
11cryoSPARC2.9initial Euler assignment
12cryoSPARC2.9final Euler assignment
13cryoSPARCclassification
14cryoSPARC3D reconstruction
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1679420
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 100919 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 6WEK

6wek

Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00917992
ELECTRON MICROSCOPYf_angle_d1.09324300
ELECTRON MICROSCOPYf_dihedral_angle_d12.87910624
ELECTRON MICROSCOPYf_chiral_restr0.0622644
ELECTRON MICROSCOPYf_plane_restr0.0092960

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