A single allosteric site merges activation, modulation & inhibition in TRPM5
In a recent Nature Chemical Biology publication, Assistant Professor, Zheng Ruan, PhD, of the Department of Biochemistry and Molecular Biology at the Sidney Kimmel Medical College, Thomas Jefferson University, and his collaborators provide a high-resolution characterization of the allosteric landscape governing the TRPM5 ion channel. TRPM5 is a monovalent cation channel activated by intracellular calcium (Ca2+), playing a pivotal role in gustatory signaling, gastrointestinal chemosensation, and pancreatic insulin secretion. The study identifies a previously uncharacterized multifunctional regulatory hub located within the upper vestibule of the S1-S4 transmembrane pocket.
By employing the non-calcium agonist CBTA, Dr. Ruan and his colleagues demonstrated that this single site integrates three distinct pharmacological functions: agonist activation, voltage-dependent modulation, and competitive inhibition. The research reveals that CBTA binding not only mimics the dual role of canonical Ca2+ binding sites but also induces a sensitive state that enables channel hyperactivation at physiological, near-resting calcium concentrations. Furthermore, the team elucidated that the inhibitor triphenylphosphine oxide targets this same site to stabilize a nonconductive conformation. By mapping this centralized allosteric hub, Dr. Ruan’s work offers a sophisticated structural framework for the development of highly specific therapeutic modulators aimed at metabolic and sensory dysregulation.