Structural energetics of cold sensitivity - PubMed
5 hours ago
- #TRPM8
- #structural biology
- #cold sensitivity
- TRPM8 is a menthol receptor activated by temperatures below 26°C, essential for cold perception.
- Combining cryogenic electron microscopy with hydrogen-deuterium exchange mass spectrometry reveals TRPM8's cold-evoked activation mechanism.
- A 'semi-swapped' architecture is identified, showing significant subunit rearrangement during activation.
- The pore and TRP helices exhibit the most significant energetic changes driving channel gating.
- Cold stabilizes the outer pore region, repositioning the S6 transmembrane helix and enabling regulatory lipid binding to open the channel.
- Comparison between human TRPM8 and its avian orthologue validates structural activation mechanisms.
- A free energy landscape and conformational pathway for cold or cooling agent activation is proposed.