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- PDB-8t4y: Human HCN1 F186C S264C C309A bound to cAMP, reconstituted in LMNG... -

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Basic information

Entry
Database: PDB / ID: 8t4y
TitleHuman HCN1 F186C S264C C309A bound to cAMP, reconstituted in LMNG + SPL
ComponentsPotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
KeywordsTRANSPORT PROTEIN / Membrane Protein / Ion Channel
Function / homology
Function and homology information


intracellular cAMP-activated cation channel activity involved in regulation of presynaptic membrane potential / HCN channels / general adaptation syndrome, behavioral process / HCN channel complex / retinal cone cell development / regulation of membrane depolarization / intracellularly cAMP-activated cation channel activity / apical protein localization / voltage-gated monoatomic cation channel activity / voltage-gated sodium channel activity ...intracellular cAMP-activated cation channel activity involved in regulation of presynaptic membrane potential / HCN channels / general adaptation syndrome, behavioral process / HCN channel complex / retinal cone cell development / regulation of membrane depolarization / intracellularly cAMP-activated cation channel activity / apical protein localization / voltage-gated monoatomic cation channel activity / voltage-gated sodium channel activity / voltage-gated potassium channel activity / potassium channel activity / sodium ion transmembrane transport / neuronal action potential / presynaptic active zone membrane / cAMP binding / cellular response to cAMP / potassium ion transmembrane transport / regulation of membrane potential / postsynaptic membrane / protein homotetramerization / axon / glutamatergic synapse / dendrite / 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 / Cyclic nucleotide-binding domain superfamily ...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
ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.58 Å
AuthorsBurtscher, V. / Mount, J. / Cowgill, J. / Chang, Y. / Bickel, K. / Yuan, P. / Chanda, B.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS101723 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM143440 United States
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis for hyperpolarization-dependent opening of human HCN1 channel.
Authors: Verena Burtscher / Jonathan Mount / Jian Huang / John Cowgill / Yongchang Chang / Kathleen Bickel / Jianhan Chen / Peng Yuan / Baron Chanda /
Abstract: Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike ...Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating charges past the charge transfer center is accompanied by concomitant unwinding of the inner end of the S4 and S5 helices, disrupting the tight gating interface observed in the Closed state structure. This helix-coil transition at the intracellular gating interface accompanies a concerted iris-like dilation of the pore helices and underlies the reversed voltage dependence of HCN channels.
History
DepositionJun 12, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 19, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)396,6768
Polymers395,3594
Non-polymers1,3174
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: 98839.758 Da / Num. of mol.: 4 / Mutation: F186C, S264C, C309A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HCN1, BCNG1 / Production host: Homo sapiens (human) / References: UniProt: O60741
#2: Chemical
ChemComp-CMP / ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / CYCLIC AMP / CAMP


Mass: 329.206 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H12N5O6P / Feature type: SUBJECT OF INVESTIGATION
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: Human HCN1 Channel / Type: COMPLEX / Details: Homomeric Tetramer / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMPotassium ChlorideKCl1
220 mMTrizma Base1
30.01 mMCyclic adenosine monophosphate1
40.2 mMMercury ChlorideHgCl1
50.025 mMLauryl Maltose Neopentyl Glycol1
67.5 uMSoy Polar Lipids1
75 uMCholesterol Hemisuccinate1
81 mMFluorinated Fos-Choline 81
SpecimenConc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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: 2400 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 53.3 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4particle selection
2EPU2image acquisition
7PHENIX1.2model fitting
9PHENIX1.2model refinement
12cryoSPARC4.4classification
13cryoSPARC4.43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 167527
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 122422 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 8T4M

8t4m


Accession code: 8T4M / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00313367
ELECTRON MICROSCOPYf_angle_d0.61518286
ELECTRON MICROSCOPYf_dihedral_angle_d12.0562080
ELECTRON MICROSCOPYf_chiral_restr0.0382131
ELECTRON MICROSCOPYf_plane_restr0.0032384

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