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- PDB-7n15: Structure of TAX-4_R421W w/cGMP open state -

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Basic information

Entry
Database: PDB / ID: 7n15
TitleStructure of TAX-4_R421W w/cGMP 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 / Activation of the phototransduction cascade / Inactivation, recovery and regulation of the phototransduction cascade / VxPx cargo-targeting to cilium / ciliary inversin compartment / multicellular organismal reproductive process / thermosensory behavior / positive regulation of growth rate / G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger ...detection of carbon dioxide / detection of chemical stimulus involved in sensory perception / Activation of the phototransduction cascade / Inactivation, recovery and regulation of the phototransduction cascade / VxPx cargo-targeting to cilium / ciliary inversin compartment / multicellular organismal reproductive process / thermosensory behavior / positive regulation of growth rate / G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger / olfactory behavior / intracellular cyclic nucleotide activated cation channel complex / intracellularly cGMP-activated cation channel activity / aerotaxis / chemosensory behavior / intracellularly cAMP-activated cation channel activity / response to oxygen levels / thermotaxis / cation channel complex / non-motile cilium / regulation of neuron differentiation / regulation of axon extension / negative regulation of cGMP-mediated signaling / monoatomic cation transmembrane transport / cGMP binding / voltage-gated potassium channel activity / phototransduction / response to hyperoxia / neuron projection morphogenesis / calcium-mediated signaling / chemotaxis / dendrite / positive regulation of gene expression / protein-containing complex binding / positive regulation of transcription by RNA polymerase II / identical protein binding / membrane / 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-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 GUANOSINE MONOPHOSPHATE / 1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE / Cyclic nucleotide-gated channel
Similarity search - Component
Biological speciesCaenorhabditis elegans (invertebrata)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 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
Revision 1.1Oct 16, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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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)356,02432
Polymers337,3404
Non-polymers18,68528
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area40100 Å2
ΔGint-182 kcal/mol
Surface area96490 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-PCG / CYCLIC GUANOSINE MONOPHOSPHATE


Mass: 345.205 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H12N5O7P
#3: Chemical
ChemComp-CPL / 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / PALMITOYL-LINOLEOYL PHOSPHATIDYLCHOLINE


Mass: 758.060 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: C42H80NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#4: Chemical
ChemComp-PX2 / 1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE


Mass: 535.671 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H52O8P / 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: Cyclic nucleotide-gated channel TAX-4 with an achromatopsia-associated missense mutation R421W
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: 69.7 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
2Leginonimage acquisition
4GctfCTF correction
7Cootmodel fitting
8PHENIXmodel fitting
10cryoSPARC2.9initial Euler assignment
11cryoSPARC2.9final Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
14PHENIXmodel refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 3988515
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 284615 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 6WEK

6wek


Accession code: 6WEK / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00618212
ELECTRON MICROSCOPYf_angle_d0.8624620
ELECTRON MICROSCOPYf_dihedral_angle_d11.74910700
ELECTRON MICROSCOPYf_chiral_restr0.0552672
ELECTRON MICROSCOPYf_plane_restr0.0082984

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