9BC6

HCN1 M305L with propofol

Summary for 9BC6

• Entry DOI: 10.2210/pdb9bc6/pdb
• EMDB information: 42116 42117 44425
• Descriptor: Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1, 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, 2,6-BIS(1-METHYLETHYL)PHENOL (3 entities in total)
• Functional Keywords: inhibitor, complex, membrane protein, nanodisc, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 305512.83

Authors

Kim, E.D.,Nimigean, C.M. (deposition date: 2024-04-07, release date: 2024-07-31, Last modification date: 2024-08-21)

Primary citation

Kim, E.D.,Wu, X.,Lee, S.,Tibbs, G.R.,Cunningham, K.P.,Di Zanni, E.,Perez, M.E.,Goldstein, P.A.,Accardi, A.,Larsson, H.P.,Nimigean, C.M.
Propofol rescues voltage-dependent gating of HCN1 channel epilepsy mutants.
Nature, 632:451-459, 2024

PubMed 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 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.

PubMed: 39085604
DOI: 10.1038/s41586-024-07743-z

Experimental method

ELECTRON MICROSCOPY (2.5 Å)