Tamsulosin ameliorates bone loss by inhibiting the release of Cl^- through wedging into an allosteric site of TMEM16A.

ABSTRACT: TMEM16A, a key calcium-activated chloride channel, is crucial for many physiological and pathological processes such as cancer, hypertension, and osteoporosis, etc. However, the regulatory mechanism of TMEM16A is poorly understood, limiting the discovery of effective modulators. Here, we unveil an allosteric gating mechanism by presenting a high-resolution cryo-EM structure of TMEM16A in complex with a channel inhibitor that we identified, Tamsulosin, which is resolved at 2.93 Å. Tamsulosin wedges itself into a pocket within the extracellular domain of TMEM16A, surrounded by α1-α2, α5-α6, and α9-α10 loops. This binding stabilizes a transient preopen conformation of TMEM16A, which is activated by Ca²⁺ ions while still preserving a closed pore to prevent Cl^- permeation.

SUBMITTER: Li S 

PROVIDER: S-EPMC11725887 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature