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- EMDB-35602: Cryo-EM structure of human HCN3 channel in apo state -

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Basic information

Entry
Database: EMDB / ID: EMD-35602
TitleCryo-EM structure of human HCN3 channel in apo state
Map data
Sample
  • Complex: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3
  • Ligand: 4-[[(2~{S},4~{a}~{R},6~{S},8~{a}~{S})-6-[(4~{S},5~{R})-4-[(2~{S})-butan-2-yl]-5,9-dimethyl-decyl]-4~{a}-methyl-2,3,4,5,6,7,8,8~{a}-octahydro-1~{H}-naphthalen-2-yl]oxy]-4-oxidanylidene-butanoic acid
Keywordshuman HCN3 channel / MEMBRANE PROTEIN
Function / homology
Function and homology information


cone cell pedicle / HCN channels / HCN channel complex / regulation of membrane depolarization / cellular response to dopamine / voltage-gated sodium channel activity / voltage-gated potassium channel activity / sodium ion transmembrane transport / cAMP binding / potassium ion transmembrane transport ...cone cell pedicle / HCN channels / HCN channel complex / regulation of membrane depolarization / cellular response to dopamine / voltage-gated sodium channel activity / voltage-gated potassium channel activity / sodium ion transmembrane transport / cAMP binding / potassium ion transmembrane transport / regulation of membrane potential / axon / neuronal cell body / dendrite / plasma membrane
Similarity search - Function
Ion transport N-terminal / Ion transport protein N-terminal / Potassium channel, voltage-dependent, EAG/ELK/ERG / 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
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.72 Å
AuthorsYu B / Lu QY / Li J / Zhang J
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Biol Chem / Year: 2024
Title: Cryo-EM structure of human HCN3 channel and its regulation by cAMP.
Authors: Bo Yu / Qiuyuan Lu / Jian Li / Xinyu Cheng / Han Hu / Yuanshuo Li / Tong Che / Yaoguang Hua / Haihai Jiang / Yuting Zhang / Cuiling Xian / Tingting Yang / Ying Fu / Yixiang Chen / Weiwei Nan ...Authors: Bo Yu / Qiuyuan Lu / Jian Li / Xinyu Cheng / Han Hu / Yuanshuo Li / Tong Che / Yaoguang Hua / Haihai Jiang / Yuting Zhang / Cuiling Xian / Tingting Yang / Ying Fu / Yixiang Chen / Weiwei Nan / Peter J McCormick / Bing Xiong / Jingjing Duan / Bo Zeng / Yanyan Li / Yang Fu / Jin Zhang /
Abstract: HCN channels are important for regulating heart rhythm and nerve activity and have been studied as potential drug targets for treating depression, arrhythmia, nerve pain, and epilepsy. Despite ...HCN channels are important for regulating heart rhythm and nerve activity and have been studied as potential drug targets for treating depression, arrhythmia, nerve pain, and epilepsy. Despite possessing unique pharmacological properties, HCN channels share common characteristics in that they are activated by hyperpolarization and modulated by cAMP and other membrane lipids. However, the mechanisms of how these ligands bind and modulate HCN channels are unclear. In this study, we solved structures of full-length human HCN3 using cryo-EM and captured two different states, including a state without any ligand bound and a state with cAMP bound. Our structures reveal the novel binding sites for cholesteryl hemisuccinate in apo state and show how cholesteryl hemisuccinate and cAMP binding cause conformational changes in different states. These findings explain how these small modulators are sensed in mammals at the molecular level. The results of our study could help to design more potent and specific compounds to influence HCN channel activity and offer new therapeutic possibilities for diseases that lack effective treatment.
History
DepositionMar 10, 2023-
Header (metadata) releaseApr 10, 2024-
Map releaseApr 10, 2024-
UpdateJul 10, 2024-
Current statusJul 10, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35602.png

Downloads & links

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Map

FileDownload / File: emd_35602.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.842 Å
Density
Contour LevelBy AUTHOR: 0.153
Minimum - Maximum-0.29800907 - 0.71765405
Average (Standard dev.)0.0040460974 (±0.020379122)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 303.12 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35602_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_35602_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Potassium/sodium hyperpolarization-activated cyclic nucleotide-ga...

EntireName: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3
Components
  • Complex: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3
  • Ligand: 4-[[(2~{S},4~{a}~{R},6~{S},8~{a}~{S})-6-[(4~{S},5~{R})-4-[(2~{S})-butan-2-yl]-5,9-dimethyl-decyl]-4~{a}-methyl-2,3,4,5,6,7,8,8~{a}-octahydro-1~{H}-naphthalen-2-yl]oxy]-4-oxidanylidene-butanoic acid

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Supramolecule #1: Potassium/sodium hyperpolarization-activated cyclic nucleotide-ga...

SupramoleculeName: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Potassium/sodium hyperpolarization-activated cyclic nucleotide-ga...

MacromoleculeName: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 86.142922 KDa
Recombinant expressionOrganism: Mammalian expression vector BsrGI-MCS-pcDNA3.1 (others)
SequenceString: MEAEQRPAAG ASEGATPGLE AVPPVAPPPA TAASGPIPKS GPEPKRRHLG TLLQPTVNKF SLRVFGSHKA VEIEQERVKS AGAWIIHPY SDFRFYWDLI MLLLMVGNLI VLPVGITFFK EENSPPWIVF NVLSDTFFLL DLVLNFRTGI VVEEGAEILL A PRAIRTRY ...String:
MEAEQRPAAG ASEGATPGLE AVPPVAPPPA TAASGPIPKS GPEPKRRHLG TLLQPTVNKF SLRVFGSHKA VEIEQERVKS AGAWIIHPY SDFRFYWDLI MLLLMVGNLI VLPVGITFFK EENSPPWIVF NVLSDTFFLL DLVLNFRTGI VVEEGAEILL A PRAIRTRY LRTWFLVDLI SSIPVDYIFL VVELEPRLDA EVYKTARALR IVRFTKILSL LRLLRLSRLI RYIHQWEEIF HM TYDLASA VVRIFNLIGM MLLLCHWDGC LQFLVPMLQD FPPDCWVSIN HMVNHSWGRQ YSHALFKAMS HMLCIGYGQQ APV GMPDVW LTMLSMIVGA TCYAMFIGHA TALIQSLDSS RRQYQEKYKQ VEQYMSFHKL PADTRQRIHE YYEHRYQGKM FDEE SILGE LSEPLREEII NFTCRGLVAH MPLFAHADPS FVTAVLTKLR FEVFQPGDLV VREGSVGRKM YFIQHGLLSV LARGA RDTR LTDGSYFGEI CLLTRGRRTA SVRADTYCRL YSLSVDHFNA VLEEFPMMRR AFETVAMDRL LRIGKKNSIL QRKRSE PSP GSSGGIMEQH LVQHDRDMAR GVRGRAPSTG AQLSGKPVLW EPLVHAPLQA AAVTSNVAIA LTHQRGPLPL SPDSPAT LL ARSAWRSAGS PASPLVPVRA GPWASTSRLP APPARTLHAS LSRAGRSQVS LLGPPPGGGG RRLGPRGRPL SASQPSLP Q RATGDGSPGR KGSGSERLPP SGLLAKPPRT AQPPRPPVPE PATPRGLQLS ANM

UniProtKB: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3

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Macromolecule #2: 4-[[(2~{S},4~{a}~{R},6~{S},8~{a}~{S})-6-[(4~{S},5~{R})-4-[(2~{S})...

MacromoleculeName: 4-[[(2~{S},4~{a}~{R},6~{S},8~{a}~{S})-6-[(4~{S},5~{R})-4-[(2~{S})-butan-2-yl]-5,9-dimethyl-decyl]-4~{a}-methyl-2,3,4,5,6,7,8,8~{a}-octahydro-1~{H}-naphthalen-2-yl]oxy]-4-oxidanylidene-butanoic acid
type: ligand / ID: 2 / Number of copies: 4 / Formula: VX9
Molecular weightTheoretical: 492.774 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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 71465
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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