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- PDB-8y60: Structural mechanism of human HCN1 hyperpolarization-activated ch... -

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Basic information

Entry
Database: PDB / ID: 8y60
TitleStructural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine
ComponentsPotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
KeywordsMEMBRANE PROTEIN / Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels / Ivabradine / complex
Function / homology
Function and homology information


: / positive regulation of membrane hyperpolarization / HCN channels / general adaptation syndrome, behavioral process / HCN channel complex / retinal cone cell development / intracellularly cAMP-activated cation channel activity / negative regulation of action potential / regulation of SA node cell action potential / regulation of membrane depolarization ...: / positive regulation of membrane hyperpolarization / HCN channels / general adaptation syndrome, behavioral process / HCN channel complex / retinal cone cell development / intracellularly cAMP-activated cation channel activity / negative regulation of action potential / regulation of SA node cell action potential / regulation of membrane depolarization / apical dendrite / maternal behavior / sodium ion import across plasma membrane / negative regulation of synaptic transmission, glutamatergic / response to L-glutamate / apical protein localization / voltage-gated monoatomic cation channel activity / voltage-gated sodium channel activity / potassium ion import across plasma membrane / phosphatidylinositol-3,4,5-trisphosphate binding / regulation of heart rate by cardiac conduction / voltage-gated potassium channel activity / potassium channel activity / neuronal action potential / cAMP binding / cellular response to interferon-beta / presynaptic active zone membrane / phosphatidylinositol-4,5-bisphosphate binding / potassium ion transmembrane transport / axon terminus / dendrite membrane / sodium ion transmembrane transport / cellular response to cAMP / dendritic shaft / regulation of membrane potential / response to calcium ion / protein homotetramerization / basolateral plasma membrane / postsynaptic membrane / axon / neuronal cell body / dendrite / glutamatergic synapse / cell surface / identical protein binding / plasma membrane
Similarity search - Function
Ion transport N-terminal / Ion transport protein N-terminal / : / Potassium channel, voltage-dependent, EAG/ELK/ERG / 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 ...Ion transport N-terminal / Ion transport protein N-terminal / : / Potassium channel, voltage-dependent, EAG/ELK/ERG / 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
CHOLESTEROL / : / Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.23 Å
AuthorsChe, T. / Cheng, X.Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Biol Chem / Year: 2024
Title: Structural mechanism of human HCN1 hyperpolarization-activated channel inhibition by ivabradine.
Authors: Tong Che / Wei Zhang / Xinyu Cheng / Sijia Lv / Minqing Zhang / Yuting Zhang / Tingting Yang / Weiwei Nan / Shuangyan Wan / Bo Zeng / Jian Li / Bing Xiong / Jin Zhang /
Abstract: The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role in regulating neuronal excitability. Despite growing evidence supporting the therapeutic potential of HCN1 ...The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role in regulating neuronal excitability. Despite growing evidence supporting the therapeutic potential of HCN1 inhibition in treating neurological disorders, the structural basis of channel inhibition by inhibitor has remained elusive. Here, we present the cryo-electron microscopy structure of human HCN1 channel in complex with inhibitor ivabradine, the drug on the market that acts on HCN channels. Combining electrophysiology, mutagenesis, and molecular dynamics simulations, our findings reveal that ivabradine binds to a previously unidentified pocket formed between the S4, S1, and HCN domain. Furthermore, through structure-based virtual screening, we identify two Food and Drug Administration-approved drugs that can inhibit the HCN1 channel by interacting with the ivabradine-binding site. Our results not only provide insights into the structural intricacies of ivabradine-mediated inhibition, but also offer a potential pharmacological framework for developing novel drugs targeting the HCN1 channel. The elucidation of these molecular interactions serves as a foundational step in advancing therapeutic strategies for modulating HCN1 activity, contributing to the broader landscape of drug discovery and development in this area.
History
DepositionFeb 1, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 29, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
B: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
C: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
D: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)399,02012
Polymers395,5994
Non-polymers3,4218
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 / Brain cyclic nucleotide-gated channel 1 / BCNG-1


Mass: 98899.789 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: O60741
#2: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C27H46O / Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-VNZ / Ivabradine / 3-[3-[[(7S)-3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-methyl-amino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one / 3-[3-[[(7S)-3,4-dimethoxy-7-bicyclo[4.2.0]octa-1(6),2,4-trienyl]methyl-methyl-amino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one


Mass: 468.585 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H36N2O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
Type: COMPLEX / Entity ID: #1 / Source: NATURAL
Molecular weightValue: 0.301 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.23 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 128643 / Symmetry type: POINT

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