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- PDB-9bc6: HCN1 M305L with propofol -

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Basic information

Entry
Database: PDB / ID: 9bc6
TitleHCN1 M305L with propofol
ComponentsPotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
KeywordsMEMBRANE PROTEIN / Inhibitor / complex / nanodisc / 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 / sodium ion transmembrane transport / cAMP binding / presynaptic active zone membrane / 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 ...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
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 2,6-BIS(1-METHYLETHYL)PHENOL / Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsKim, E.D. / Nimigean, C.M.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM124451 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS137561 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
DepositionApr 7, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
Revision 1.1Aug 14, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.2Aug 21, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)305,51316
Polymers298,5034
Non-polymers7,01012
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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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: 74625.695 Da / Num. of mol.: 4 / Mutation: M305L
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-PCW / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / (Z,Z)-4-HYDROXY-N,N,N-TRIMETHYL-10-OXO-7-[(1-OXO-9-OCTADECENYL)OXY]-3,5,9-TRIOXA-4-PHOSPHAHEPTACOS-18-EN-1-AMINIUM-4-OXIDE


Mass: 787.121 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C44H85NO8P / Comment: DOPC, phospholipid*YM
#3: Chemical
ChemComp-PFL / 2,6-BIS(1-METHYLETHYL)PHENOL / 2,6-DIISOPROPYLPHENOL / PROPOFOL


Mass: 178.271 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H18O / 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: HCN1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3200 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 48.48 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21rc1_5109: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 217000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00514948
ELECTRON MICROSCOPYf_angle_d0.78920340
ELECTRON MICROSCOPYf_dihedral_angle_d6.0912096
ELECTRON MICROSCOPYf_chiral_restr0.0542276
ELECTRON MICROSCOPYf_plane_restr0.0082584

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