File Download
There are no files associated with this item.
Links for fulltext
(May Require Subscription)
- Publisher Website: 10.1038/s41467-022-30479-1
- Scopus: eid_2-s2.0-85130357764
- PMID: 35589730
Supplementary
- Citations:
- Appears in Collections:
Article: Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC
Title | Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC |
---|---|
Authors | |
Issue Date | 2022 |
Citation | Nature Communications, 2022, v. 13, n. 1, article no. 2798 How to Cite? |
Abstract | 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. |
Persistent Identifier | http://hdl.handle.net/10722/343374 |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lam, Andy K.M. | - |
dc.contributor.author | Rutz, Sonja | - |
dc.contributor.author | Dutzler, Raimund | - |
dc.date.accessioned | 2024-05-10T09:07:35Z | - |
dc.date.available | 2024-05-10T09:07:35Z | - |
dc.date.issued | 2022 | - |
dc.identifier.citation | Nature Communications, 2022, v. 13, n. 1, article no. 2798 | - |
dc.identifier.uri | http://hdl.handle.net/10722/343374 | - |
dc.description.abstract | 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. | - |
dc.language | eng | - |
dc.relation.ispartof | Nature Communications | - |
dc.title | Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1038/s41467-022-30479-1 | - |
dc.identifier.pmid | 35589730 | - |
dc.identifier.scopus | eid_2-s2.0-85130357764 | - |
dc.identifier.volume | 13 | - |
dc.identifier.issue | 1 | - |
dc.identifier.spage | article no. 2798 | - |
dc.identifier.epage | article no. 2798 | - |
dc.identifier.eissn | 2041-1723 | - |