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- EMDB-8512: Structure of the human HCN1 hyperpolarization-activated cyclic nu... -

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Basic information

Entry
Database: EMDB / ID: EMD-8512
TitleStructure of the human HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP
Map dataHuman HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP, low-pass filtered to 3.51 A, B-factor sharpened at -120 A2
Sample
  • Organelle or cellular component: Human HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
  • Ligand: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE
Keywordspacemaker ion channel / TRANSPORT PROTEIN
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 / intracellularly cAMP-activated cation channel activity / regulation of membrane depolarization / 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 / intracellularly cAMP-activated cation channel activity / regulation of membrane depolarization / apical protein localization / voltage-gated monoatomic cation channel activity / voltage-gated sodium channel activity / voltage-gated potassium channel activity / potassium channel activity / neuronal action potential / cAMP binding / presynaptic active zone membrane / cellular response to cAMP / potassium ion transmembrane transport / sodium ion transmembrane transport / regulation of membrane potential / protein homotetramerization / postsynaptic membrane / axon / dendrite / glutamatergic synapse / 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: 3.51 Å
AuthorsLee C-H / MacKinnon R
CitationJournal: Cell / Year: 2017
Title: Structures of the Human HCN1 Hyperpolarization-Activated Channel.
Authors: Chia-Hsueh Lee / Roderick MacKinnon /
Abstract: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels underlie the control of rhythmic activity in cardiac and neuronal pacemaker cells. In HCN, the polarity of voltage dependence is ...Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels underlie the control of rhythmic activity in cardiac and neuronal pacemaker cells. In HCN, the polarity of voltage dependence is uniquely reversed. Intracellular cyclic adenosine monophosphate (cAMP) levels tune the voltage response, enabling sympathetic nerve stimulation to increase the heart rate. We present cryo-electron microscopy structures of the human HCN channel in the absence and presence of cAMP at 3.5 Å resolution. HCN channels contain a K channel selectivity filter-forming sequence from which the amino acids create a unique structure that explains Na and K permeability. The voltage sensor adopts a depolarized conformation, and the pore is closed. An S4 helix of unprecedented length extends into the cytoplasm, contacts the C-linker, and twists the inner helical gate shut. cAMP binding rotates cytoplasmic domains to favor opening of the inner helical gate. These structures advance understanding of ion selectivity, reversed polarity gating, and cAMP regulation in HCN channels.
History
DepositionDec 8, 2016-
Header (metadata) releaseJan 25, 2017-
Map releaseJan 25, 2017-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.04
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  • Surface view with fitted model
  • Atomic models: PDB-5u6p
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8512.png

Downloads & links

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Map

FileDownload / File: emd_8512.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP, low-pass filtered to 3.51 A, B-factor sharpened at -120 A2
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 240 pix.
= 312. Å		1.3 Å/pix.
x 240 pix.
= 312. Å		1.3 Å/pix.
x 240 pix.
= 312. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.3 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04 / Movie #1: 0.04
Minimum - Maximum-0.1138283 - 0.20777284
Average (Standard dev.)0.00003660873 (±0.0065714433)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 312.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.31.31.3
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z312.000312.000312.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.1140.2080.000

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Supplemental data

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Additional map: Human HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in...

Fileemd_8512_additional.map
AnnotationHuman HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP: unfiltered, unsharpened map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human HCN1 hyperpolarization-activated cyclic nucleotide-gated io...

EntireName: Human HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP
Components
  • Organelle or cellular component: Human HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
  • Ligand: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE

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Supramolecule #1: Human HCN1 hyperpolarization-activated cyclic nucleotide-gated io...

SupramoleculeName: Human HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP
type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
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 11
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 74.643734 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 NVASDTVFLL DLIMNFRTGT VNEDSSEIIL DPKVIKMNYL KSWFVVDFIS SIPVDYIFLI VE KGMDSEV YKTARALRIV RFTKILSLLR 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 QAALPRE SS SVLNTDPDAE KPRFASNL

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

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Macromolecule #2: Potassium/sodium hyperpolarization-activated cyclic nucleotide-ga...

MacromoleculeName: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.635006 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)

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

MacromoleculeName: ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / type: ligand / ID: 3 / 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

Concentration5 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 1.78 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.3000000000000003 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.51 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 125339
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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