9P3P

Zebrafish TRPM5 with 5mM EGTA and 0.5mM CBTA

This is a non-PDB format compatible entry.

Summary for 9P3P

• Entry DOI: 10.2210/pdb9p3p/pdb
• EMDB information: 71250
• Descriptor: Green fluorescent protein,Transient receptor potential cation channel subfamily M member 5, 2-acetamido-2-deoxy-beta-D-glucopyranose, (2R)-2-(hydroxymethyl)-4-{[(25R)-10alpha,14beta,17beta-spirost-5-en-3beta-yl]oxy}butyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside, ... (5 entities in total)
• Functional Keywords: trpm5 channel; ion channel; cation channel; sodium channel; calcium; cbta, transport protein
• Biological source: Danio rerio (zebrafish); More
• Total number of polymer chains: 4
• Total formula weight: 674435.05

Authors

Ruan, Z.,Du, J.,Lu, W. (deposition date: 2025-06-14, release date: 2026-01-07, Last modification date: 2026-01-21)

Primary citation

Ruan, Z.,Lee, J.,Li, Y.,Orozco, I.J.,Du, J.,Lu, W.
A single allosteric site merges activation, modulation and inhibition in TRPM5.
Nat.Chem.Biol., 2026

PubMed Abstract: TRPM5 is a Ca-activated monovalent cation channel essential for taste perception, insulin secretion and gastrointestinal chemosensation. Canonical TRPM5 activation requires Ca binding at two distinct sites: an agonist site within the lower vestibule of the S1-S4 pocket in the transmembrane domain (Ca) and a modulatory site in the intracellular domain (Ca) that tunes voltage dependence and agonist sensitivity. Here we characterize CBTA as a noncalcium agonist that binds to the upper vestibule of the S1-S4 pocket, directly above Ca. CBTA alone mimics the dual role of Ca and Ca, merging agonist activation with voltage modulation. CBTA also renders TRPM5 supersensitive to Ca, synergistically hyperactivating the channel even at near-resting Ca levels. We further demonstrate that the inhibitor triphenylphosphine oxide binds the same site but stabilizes a nonconductive state. These opposing effects reveal the upper S1-S4 pocket as a multifunctional regulatory hub integrating activation, inhibition and modulation in TRPM5.

PubMed: 41491833
DOI: 10.1038/s41589-025-02097-7

Experimental method

ELECTRON MICROSCOPY (3 Å)