+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-35602 | |||||||||
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Title | Cryo-EM structure of human HCN3 channel in apo state | |||||||||
Map data | ||||||||||
Sample |
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Keywords | human 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 | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.72 Å | |||||||||
Authors | Yu B / Lu QY / Li J / Zhang J | |||||||||
Funding support | 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_35602.map.gz | 167.7 MB | EMDB map data format | |
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Header (meta data) | emd-35602-v30.xml emd-35602.xml | 14.9 KB 14.9 KB | Display Display | EMDB header |
Images | emd_35602.png | 32.3 KB | ||
Filedesc metadata | emd-35602.cif.gz | 5.8 KB | ||
Others | emd_35602_half_map_1.map.gz emd_35602_half_map_2.map.gz | 164.3 MB 164.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-35602 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-35602 | HTTPS FTP |
-Related structure data
Related structure data | 8inzMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_35602.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.842 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_35602_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_35602_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Potassium/sodium hyperpolarization-activated cyclic nucleotide-ga...
Entire | Name: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 |
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Components |
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-Supramolecule #1: Potassium/sodium hyperpolarization-activated cyclic nucleotide-ga...
Supramolecule | Name: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Potassium/sodium hyperpolarization-activated cyclic nucleotide-ga...
Macromolecule | Name: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 86.142922 KDa |
Recombinant expression | Organism: Mammalian expression vector BsrGI-MCS-pcDNA3.1 (others) |
Sequence | String: 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 |
-Macromolecule #2: 4-[[(2~{S},4~{a}~{R},6~{S},8~{a}~{S})-6-[(4~{S},5~{R})-4-[(2~{S})...
Macromolecule | Name: 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 |
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Molecular weight | Theoretical: 492.774 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination 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 |
-Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 71465 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |