[English] 日本語
Yorodumi Papers
- Database of articles cited by EMDB/PDB/SASBDB data -

+
Search query

Keywords
Structure methods
Author
Journal
IF

-
Structure paper

TitlePropofol rescues voltage-dependent gating of HCN1 channel epilepsy mutants.
Journal, issue, pagesNature, Vol. 632, Issue 8024, Page 451-459, Year 2024
Publish dateJul 31, 2024
AuthorsElizabeth 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 /
PubMed AbstractHyperpolarization-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.
External linksNature / PubMed:39085604
MethodsEM (single particle)
Resolution2.5 - 3.3 Å
Structure data

42116

8uc7

EMDB-42116, PDB-8uc7:
HCN1 complex with propofol
Method: EM (single particle) / Resolution: 2.9 Å

42117

8uc8

EMDB-42117, PDB-8uc8:
HCN1 nanodisc
Method: EM (single particle) / Resolution: 3.0 Å

44425

9bc6

EMDB-44425, PDB-9bc6:
HCN1 M305L with propofol
Method: EM (single particle) / Resolution: 2.5 Å

44426

9bc7

EMDB-44426, PDB-9bc7:
HCN1 M305L holo
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

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

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

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

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN/INHIBITOR / inhibitor / complex / plasma membrane / cyclic nucleotide / TRANSPORT PROTEIN-INHIBITOR complex / TRANSPORT PROTEIN / membrane protein / nanodisc

+
About Yorodumi Papers

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbjlc1.pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi Papers

Database of articles cited by EMDB/PDB/SASBDB data

  • Database of articles cited by EMDB, PDB, and SASBDB entries
  • Using PubMed data

Related info.:EMDB / PDB / SASBDB / Yorodumi / EMN Papers / Changes in new EM Navigator and Yorodumi

Read more