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- EMDB-42116: HCN1 complex with propofol -

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Basic information

Entry
Database: EMDB / ID: EMD-42116
TitleHCN1 complex with propofol
Map data
Sample
  • Complex: HCN1 with propofol
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
  • Ligand: 2,6-BIS(1-METHYLETHYL)PHENOL
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Keywordsinhibitor / complex / plasma membrane / cyclic nucleotide / TRANSPORT PROTEIN-INHIBITOR complex
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 / neuronal action potential / sodium ion transmembrane transport / cAMP binding / cellular response to cAMP / presynaptic active zone membrane / 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 ...: / 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: 2.9 Å
AuthorsKim ED / Nimigean CM
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM124451 United States
CitationJournal: Nature / Year: 2024
Title: Propofol rescues voltage-dependent gating of HCN1 channel epilepsy mutants.
Authors: Elizabeth D Kim / Xiaoan Wu / Sangyun Lee / Gareth R Tibbs / Kevin P Cunningham / Eleonora Di Zanni / Marta E Perez / Peter A Goldstein / Alessio Accardi / H Peter Larsson / Crina M Nimigean /
Abstract: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential for pacemaking activity and neural signalling. Drugs inhibiting HCN1 are promising candidates for management of ...Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential for pacemaking activity and neural signalling. Drugs inhibiting HCN1 are promising candidates for management of neuropathic pain and epileptic seizures. The general anaesthetic propofol (2,6-di-iso-propylphenol) is a known HCN1 allosteric inhibitor with unknown structural basis. Here, using single-particle cryo-electron microscopy and electrophysiology, we show that propofol inhibits HCN1 by binding to a mechanistic hotspot in a groove between the S5 and S6 transmembrane helices. We found that propofol restored voltage-dependent closing in two HCN1 epilepsy-associated polymorphisms that act by destabilizing the channel closed state: M305L, located in the propofol-binding site in S5, and D401H in S6 (refs. ). To understand the mechanism of propofol inhibition and restoration of voltage-gating, we tracked voltage-sensor movement in spHCN channels and found that propofol inhibition is independent of voltage-sensor conformational changes. Mutations at the homologous methionine in spHCN and an adjacent conserved phenylalanine in S6 similarly destabilize closing without disrupting voltage-sensor movements, indicating that voltage-dependent closure requires this interface intact. We propose a model for voltage-dependent gating in which propofol stabilizes coupling between the voltage sensor and pore at this conserved methionine-phenylalanine interface in HCN channels. These findings unlock potential exploitation of this site to design specific drugs targeting HCN channelopathies.
History
DepositionSep 25, 2023-
Header (metadata) releaseJul 31, 2024-
Map releaseJul 31, 2024-
UpdateAug 21, 2024-
Current statusAug 21, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42116.png

Downloads & links

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Map

FileDownload / File: emd_42116.map.gz / Format: CCP4 / Size: 149.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.815 Å
Density
Contour LevelBy AUTHOR: 0.00791
Minimum - Maximum-0.062283576 - 0.08297968
Average (Standard dev.)0.00013229303 (±0.001723016)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions340340340
Spacing340340340
CellA=B=C: 277.1 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_42116_additional_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_42116_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_42116_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : HCN1 with propofol

EntireName: HCN1 with propofol
Components
  • Complex: HCN1 with propofol
    • Protein or peptide: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
  • Ligand: 2,6-BIS(1-METHYLETHYL)PHENOL
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

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Supramolecule #1: HCN1 with propofol

SupramoleculeName: HCN1 with propofol / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
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: 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: 2,6-BIS(1-METHYLETHYL)PHENOL

MacromoleculeName: 2,6-BIS(1-METHYLETHYL)PHENOL / type: ligand / ID: 2 / Number of copies: 4 / Formula: PFL
Molecular weightTheoretical: 178.271 Da
Chemical component information

ChemComp-PFL:
2,6-BIS(1-METHYLETHYL)PHENOL

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Macromolecule #3: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 3 / Number of copies: 12 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

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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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 52.53 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 415000
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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