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Structure of human TRPM8 channel.
Sergii Palchevskyi1,2, Mariusz Czarnocki-Cieciura1, Giulio Vistoli3
1Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, 02-109, Warsaw, Poland.
Communications Biology
|October 19, 2023
Summary
Researchers visualized the human TRPM8 channel in its closed state using cryo-electron microscopy. This provides insights into TRPM8 channel structure and interactions, aiding anticancer drug development.
Area of Science:
- Structural biology
- Molecular biophysics
- Ion channel research
Background:
- Transient Receptor Potential Melastatin 8 (TRPM8) is a non-selective cation channel activated by various stimuli.
- TRPM8 is a significant therapeutic target for anticancer drug development and managing pathological conditions.
Purpose of the Study:
- To determine the high-resolution cryo-electron microscopy structure of the human TRPM8 channel in the closed state.
- To elucidate the structural basis of TRPM8 channel function and interactions with ligands like icilin.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was employed to solve the structure of the human TRPM8 channel.
- High-resolution structural analysis at 2.7 Å resolution.
- Molecular modeling and comparative analysis of TRPM pore helices.
Main Results:
- A 2.7 Å resolution cryo-EM structure of the human TRPM8 channel in the closed state was obtained.
- The most complete model of the N-terminal pre-melastatin homology region was achieved.
- Interactions with lipids and the modulator icilin were visualized and modeled.
Conclusions:
- The determined structure provides a detailed view of the closed TRPM8 channel, including its N-terminal region and lipid interactions.
- Analysis of pore helix conformations in TRPM structures allows classification into closed, desensitized, and open states.
- This structural information is crucial for understanding TRPM8 channel gating and for designing targeted therapeutics.
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