7ZK3
Structure of 1PBC- and calcium-bound mTMEM16A(ac) chloride channel at 2.85 A resolution
Summary for 7ZK3
| Entry DOI | 10.2210/pdb7zk3/pdb |
| EMDB information | 14753 |
| Descriptor | Anoctamin-1, CALCIUM ION, 1-Hydroxy-3-(trifluoromethyl)pyrido[1,2-a]benzimidazole-4-carbonitrile (3 entities in total) |
| Functional Keywords | calcium-activated chloride channel, anoctamin-1, membrane protein |
| Biological source | Mus musculus (house mouse) |
| Total number of polymer chains | 2 |
| Total formula weight | 222912.85 |
| Authors | Lam, A.K.M.,Rutz, S.,Dutzler, R. (deposition date: 2022-04-12, release date: 2022-05-25, Last modification date: 2024-11-20) |
| Primary citation | Lam, A.K.M.,Rutz, S.,Dutzler, R. Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC. Nat Commun, 13:2798-2798, 2022 Cited by PubMed 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. PubMed: 35589730DOI: 10.1038/s41467-022-30479-1 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.85 Å) |
Structure validation
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