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- PDB-5u6p: Structure of the human HCN1 hyperpolarization-activated cyclic nu... -

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Basic information

Entry
Database: PDB / ID: 5u6p
TitleStructure of the human HCN1 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP
Components(Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11) x 2
KeywordsTRANSPORT PROTEIN / pacemaker ion channel
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 / dendrite membrane / axon terminus / 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
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: 3.51 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, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Author supporting evidence / Data collection / Category: em_image_scans / pdbx_audit_support
Revision 1.2Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Assembly

Deposited unit
A: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
E: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
B: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
F: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
C: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
G: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
D: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
H: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)306,43212
Polymers305,1158
Non-polymers1,3174
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.007682, 0.999958, -0.005088), (-0.999966, -0.007696, -0.002854), (-0.002893, 0.005066, 0.999983)0.52019, 122.84318, -0.20262
3given(-0.999982, -0.00533, -0.002917), (0.005334, -0.999985, -0.001227), (-0.00291, -0.001242, 0.999995)122.48782, 121.97884, 0.20527
4given(0.008326, -0.99995, -0.005461), (0.999964, 0.008335, -0.001634), (0.00168, -0.005447, 0.999984)121.74802, -0.28717, 0.1402
DetailsThe structure is a tetramer. Chains E, F, G, and H are portions of chains A, B, C, and D, respectively, that are modeled separately.

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Components

#1: Protein
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11 / Brain cyclic nucleotide-gated channel 1 / BCNG-1


Mass: 74643.734 Da / Num. of mol.: 4 / Fragment: UNP residues 1-635,866-890
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: Protein/peptide
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 11 / Brain cyclic nucleotide-gated channel 1


Mass: 1635.006 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HCN1, BCNG1 / Production host: Homo sapiens (human)
#3: Chemical
ChemComp-CMP / ADENOSINE-3',5'-CYCLIC-MONOPHOSPHATE / CYCLIC AMP / CAMP


Mass: 329.206 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: C10H12N5O6P
Sequence detailsChains E, F, G, and H are residues ~615 to ~633 (uncertain register) of chains A, B, C, and D. They ...Chains E, F, G, and H are residues ~615 to ~633 (uncertain register) of chains A, B, C, and D. They are represented as separate chains at the authors' request.

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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 hyperpolarization-activated cyclic nucleotide-gated ion channel in complex with cAMP
Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Plasmid: pEG_BacMam
Buffer solutionpH: 8
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
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: 3300 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 1.78 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.51 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 125339 / Symmetry type: POINT

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