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- EMDB-41036: Closed human HCN1 F186C S264C bound to cAMP, reconstituted in LMN... -

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Basic information

Entry
Database: EMDB / ID: EMD-41036
TitleClosed human HCN1 F186C S264C bound to cAMP, reconstituted in LMNG + SPL
Map data
Sample
  • Complex: Tetrameric hHCN1
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
  • Ligand: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE
KeywordsIon Channel / TRANSPORT PROTEIN
Function / homology
Function and homology information


intracellular cAMP-activated cation channel activity involved in regulation of presynaptic membrane potential / 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 ...intracellular cAMP-activated cation channel activity involved in regulation of presynaptic membrane potential / 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 / axon terminus / dendrite membrane / potassium ion transmembrane transport / 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
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.16 Å
AuthorsBurtscher V / Mount J / Cowgill J / Chang Y / Bickel K / Yuan P / Chanda B
Funding support United States, 2 items
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 9, 2023-
Header (metadata) releaseJun 12, 2024-
Map releaseJun 12, 2024-
UpdateJul 3, 2024-
Current statusJul 3, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41036.png

Downloads & links

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Map

FileDownload / File: emd_41036.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 300 pix.
= 278.4 Å		0.93 Å/pix.
x 300 pix.
= 278.4 Å		0.93 Å/pix.
x 300 pix.
= 278.4 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.928 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.60431904 - 1.0702261
Average (Standard dev.)0.00076138094 (±0.02699479)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 278.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_41036_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_41036_half_map_2.map
Projections & Slices
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Sample components

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Entire : Tetrameric hHCN1

EntireName: Tetrameric hHCN1
Components
  • Complex: Tetrameric hHCN1
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
  • Ligand: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

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Supramolecule #1: Tetrameric hHCN1

SupramoleculeName: Tetrameric hHCN1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 / Details: Homotetramer
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 1
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 98.87182 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEGGGKPNSS SNSRDDGNSV FPAKASATGA GPAAAEKRLG TPPGGGGAGA KEHGNSVCFK VDGGGGGGGG GGGGEEPAGG FEDAEGPRR QYGFMQRQFT SMLQPGVNKF SLRMFGSQKA VEKEQERVKT AGFWIIHPYS DFRFYWDLIM LIMMVGNLVI I PVGITFFT ...String:
MEGGGKPNSS SNSRDDGNSV FPAKASATGA GPAAAEKRLG TPPGGGGAGA KEHGNSVCFK VDGGGGGGGG GGGGEEPAGG FEDAEGPRR QYGFMQRQFT SMLQPGVNKF SLRMFGSQKA VEKEQERVKT AGFWIIHPYS DFRFYWDLIM LIMMVGNLVI I PVGITFFT EQTTTPWIIF NVASDTVCLL DLIMNFRTGT VNEDSSEIIL DPKVIKMNYL KSWFVVDFIS SIPVDYIFLI VE KGMDSEV YKTARALRIV RFTKILCLLR LLRLSRLIRY IHQWEEIFHM TYDLASAVVR IFNLIGMMLL LCHWDGCLQF LVP LLQDFP PDCWVSLNEM VNDSWGKQYS YALFKAMSHM LCIGYGAQAP VSMSDLWITM LSMIVGATCY AMFVGHATAL IQSL DSSRR QYQEKYKQVE QYMSFHKLPA DMRQKIHDYY EHRYQGKIFD EENILNELND PLREEIVNFN CRKLVATMPL FANAD PNFV TAMLSKLRFE VFQPGDYIIR EGAVGKKMYF IQHGVAGVIT KSSKEMKLTD GSYFGEICLL TKGRRTASVR ADTYCR LYS LSVDNFNEVL EEYPMMRRAF ETVAIDRLDR IGKKNSILLQ KFQKDLNTGV FNNQENEILK QIVKHDREMV QAIAPIN YP QMTTLNSTSS TTTPTSRMRT QSPPVYTATS LSHSNLHSPS PSTQTPQPSA ILSPCSYTTA VCSPPVQSPL AARTFHYA S PTASQLSLMQ QQPQQQVQQS QPPQTQPQQP SPQPQTPGSS TPKNEVHKST QALHNTNLTR EVRPLSASQP SLPHEVSTL ISRPHPTVGE SLASIPQPVT AVPGTGLQAG GRSTVPQRVT LFRQMSSGAI PPNRGVPPAP PPPAAALPRE SSSVLNTDPD AEKPRFASN L

UniProtKB: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1

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Macromolecule #2: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

MacromoleculeName: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / type: ligand / ID: 2 / Number of copies: 4 / Formula: CMP
Molecular weightTheoretical: 329.206 Da
Chemical component information

ChemComp-CMP:
ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

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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

Concentration2.5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMKClPotassium Chloride
20.0 mMTris-HCl
2.0 mMDithiothreitol
25.0 uMLauryl Maltose Neopentyl Glycol
5.4 uMCholesteryl Hemisuccinate
7.5 uMSoy Polar Lipids
10.0 uMCyclic Adenosine Monophosphate
200.0 uMHgClMercury Chloride
GridModel: Quantifoil / Material: COPPER / Mesh: 200
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 4 K / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 1973 / Average exposure time: 9.77 sec. / Average electron dose: 53.07 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.4 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm

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Image processing

Particle selectionNumber selected: 698029
Startup modelType of model: NONE
Final reconstructionNumber classes used: 2 / Applied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.1) / Number images used: 88923
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC (ver. 4.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

5u6p


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8t4m:
Closed human HCN1 F186C S264C bound to cAMP, reconstituted in LMNG + SPL

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