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Updated: Jun 28, 2025

Expression and Purification of the Human Lipid-sensitive Cation Channel TRPC3 for Structural Determination by Single-particle Cryo-electron Microscopy
08:27

Expression and Purification of the Human Lipid-sensitive Cation Channel TRPC3 for Structural Determination by Single-particle Cryo-electron Microscopy

Published on: January 7, 2019

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Cryo-EM structure of human HCN3 channel and its regulation by cAMP

Bo Yu1, Qiuyuan Lu2, Jian Li3

  • 1The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China; The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.

The Journal of Biological Chemistry
|April 18, 2024
PubMed

Insights

Structural insights into human HCN3 channels reveal novel ligand binding sites. This research clarifies how cholesteryl hemisuccinate and cAMP modulate these channels, paving the way for new therapeutic strategies.

Area of Science:

  • Molecular biology
  • Structural biology
  • Pharmacology

Background:

  • Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate heart rhythm and nerve activity.
  • HCN channels are therapeutic targets for neurological and cardiac conditions, including epilepsy, pain, and arrhythmia.
  • Mechanisms of ligand binding and modulation of HCN channels remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms of ligand binding and modulation in human HCN3 channels.
  • To determine the structural basis for HCN channel regulation by small molecules.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to solve the structures of full-length human HCN3.
  • Two distinct conformational states were captured: apo (ligand-free) and cAMP-bound.

Main Results:

  • Novel binding sites for cholesteryl hemisuccinate in the apo state were identified.
  • Structures reveal how cholesteryl hemisuccinate and cAMP binding induce conformational changes.
  • Molecular-level understanding of how small modulators are sensed by HCN channels in mammals.

Conclusions:

  • The study provides key structural insights into HCN3 channel gating and modulation.
  • Findings facilitate the design of more potent and specific modulators of HCN channel activity.
  • Offers potential for new therapeutic interventions for diseases involving HCN channel dysfunction.

Keywords:
CHSHCN3 channelRegulationcAMPcryo-EM

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