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TitleInhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 2798, Year 2022
Publish dateMay 19, 2022
AuthorsAndy K M Lam / Sonja Rutz / Raimund Dutzler /
PubMed AbstractTMEM16A, a calcium-activated chloride channel involved in multiple cellular processes, is a proposed target for diseases such as hypertension, asthma, and cystic fibrosis. Despite these therapeutic ...TMEM16A, a calcium-activated chloride channel involved in multiple cellular processes, is a proposed target for diseases such as hypertension, asthma, and cystic fibrosis. Despite these therapeutic promises, its pharmacology remains poorly understood. Here, we present a cryo-EM structure of TMEM16A in complex with the channel blocker 1PBC and a detailed functional analysis of its inhibition mechanism. A pocket located external to the neck region of the hourglass-shaped pore is responsible for open-channel block by 1PBC and presumably also by its structural analogs. The binding of the blocker stabilizes an open-like conformation of the channel that involves a rearrangement of several pore helices. The expansion of the outer pore enhances blocker sensitivity and enables 1PBC to bind at a site within the transmembrane electric field. Our results define the mechanism of inhibition and gating and will facilitate the design of new, potent TMEM16A modulators.
External linksNat Commun / PubMed:35589730 / PubMed Central
MethodsEM (single particle)
Resolution2.85 Å
Structure data

14753

7zk3

EMDB-14753: Cryo-EM map of 1PBC- and calcium-bound mTMEM16A(ac) chloride channel at 2.85 A resolution
PDB-7zk3: Structure of 1PBC- and calcium-bound mTMEM16A(ac) chloride channel at 2.85 A resolution
Method: EM (single particle) / Resolution: 2.85 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-JRF:
1-Hydroxy-3-(trifluoromethyl)pyrido[1,2-a]benzimidazole-4-carbonitrile

Source
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / calcium-activated chloride channel / anoctamin-1

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