9O8F

Cryo-EM structure of primidone-bound rabbit TRPM3 having 2 resting and 2 activated subunits (para position) at 18 degrees Celsius

This is a non-PDB format compatible entry.

Summary for 9O8F

• Entry DOI: 10.2210/pdb9o8f/pdb
• EMDB information: 70225
• Descriptor: TRPM3, CHOLESTEROL HEMISUCCINATE, primidone (3 entities in total)
• Functional Keywords: trpm3, ion channel, membrane protein
• Biological source: Oryctolagus cuniculus
• Total number of polymer chains: 4
• Total formula weight: 612021.94

Authors

Kumar, S.,Lu, W.,Du, J. (deposition date: 2025-04-15, release date: 2025-12-17, Last modification date: 2026-02-04)

Primary citation

Kumar, S.,Jin, F.,Park, S.J.,Choi, W.,Keuning, S.I.,Massimino, R.P.,Vu, S.,Lu, W.,Du, J.
Structural basis for agonist and heat activation of nociceptor TRPM3.
Nat.Struct.Mol.Biol., 33:34-42, 2026

PubMed Abstract: Detecting noxious heat is vital for survival, triggering protective pain responses. The TRPM3 channel is a key nociceptor and a promising therapeutic target for pain and neurological disorders. Here we show that the rabbit TRPM3 is intrinsically dynamic, with its intracellular domain (ICD) sampling both resting and activated states, but favoring the resting state in the absence of stimulation. We reveal that heat and the synthetic agonist CIM0216 shift the equilibrium toward activation by inducing a similar ICD rearrangement. Mutations that facilitate ICD movement enhance sensitivity to both thermal and chemical stimuli, underscoring the central role of the ICD in channel gating. We also show that the antagonist primidone binds the same site as CIM0216 in the S1-S4 domain but inhibits channel activation. This study provides a structural framework for a mechanistic understanding of thermal and chemical gating of TRPM3 and for guiding the rational design of TRPM3-targeted analgesics and neurotherapeutics.

PubMed: 41136608
DOI: 10.1038/s41594-025-01692-5

Experimental method

ELECTRON MICROSCOPY (3.91 Å)