A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels
<jats:p>Potassium (K<jats:sup>+</jats:sup>) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) tha...
| Những tác giả chính: | , , , , , , , , , , , , , , , , , , , , , |
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| Định dạng: | Journal article |
| Ngôn ngữ: | English |
| Được phát hành: |
American Association for the Advancement of Science
2019
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| _version_ | 1826269138913329152 |
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| author | Schewe, M Sun, H Mert, Ü Mackenzie, A Pike, A Schulz, F Constantin, C Vowinkel, K Conrad, L Kiper, A Gonzalez, W Musinszki, M Tegtmeier, M Pryde, D Belabed, H Nazare, M De Groot, B Decher, N Fakler, B Carpenter, E Tucker, S Baukrowitz, T |
| author_facet | Schewe, M Sun, H Mert, Ü Mackenzie, A Pike, A Schulz, F Constantin, C Vowinkel, K Conrad, L Kiper, A Gonzalez, W Musinszki, M Tegtmeier, M Pryde, D Belabed, H Nazare, M De Groot, B Decher, N Fakler, B Carpenter, E Tucker, S Baukrowitz, T |
| author_sort | Schewe, M |
| collection | OXFORD |
| description | <jats:p>Potassium (K<jats:sup>+</jats:sup>) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K<jats:sup>+</jats:sup> channels gated at their selectivity filter (SF), including many two-pore domain K<jats:sup>+</jats:sup> (K<jats:sub>2P</jats:sub>) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca<jats:sup>2+</jats:sup>)–activated big-conductance potassium (BK)–type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K<jats:sup>+</jats:sup> occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K<jats:sup>+</jats:sup> channel activators and highlight a filter gating machinery that is conserved across different families of K<jats:sup>+</jats:sup> channels with implications for rational drug design.</jats:p> |
| first_indexed | 2024-03-06T21:20:22Z |
| format | Journal article |
| id | oxford-uuid:413f89cf-1e16-47fb-83e1-5a0b532b5cab |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:20:22Z |
| publishDate | 2019 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | oxford-uuid:413f89cf-1e16-47fb-83e1-5a0b532b5cab2022-03-26T14:42:30ZA pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channelsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:413f89cf-1e16-47fb-83e1-5a0b532b5cabEnglishSymplectic Elements at OxfordAmerican Association for the Advancement of Science2019Schewe, MSun, HMert, ÜMackenzie, APike, ASchulz, FConstantin, CVowinkel, KConrad, LKiper, AGonzalez, WMusinszki, MTegtmeier, MPryde, DBelabed, HNazare, MDe Groot, BDecher, NFakler, BCarpenter, ETucker, SBaukrowitz, T<jats:p>Potassium (K<jats:sup>+</jats:sup>) channels have been evolutionarily tuned for activation by diverse biological stimuli, and pharmacological activation is thought to target these specific gating mechanisms. Here we report a class of negatively charged activators (NCAs) that bypass the specific mechanisms but act as master keys to open K<jats:sup>+</jats:sup> channels gated at their selectivity filter (SF), including many two-pore domain K<jats:sup>+</jats:sup> (K<jats:sub>2P</jats:sub>) channels, voltage-gated hERG (human ether-à-go-go–related gene) channels and calcium (Ca<jats:sup>2+</jats:sup>)–activated big-conductance potassium (BK)–type channels. Functional analysis, x-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the SF, increase pore and SF K<jats:sup>+</jats:sup> occupancy, and open the filter gate. These results uncover an unrecognized polypharmacology among K<jats:sup>+</jats:sup> channel activators and highlight a filter gating machinery that is conserved across different families of K<jats:sup>+</jats:sup> channels with implications for rational drug design.</jats:p> |
| spellingShingle | Schewe, M Sun, H Mert, Ü Mackenzie, A Pike, A Schulz, F Constantin, C Vowinkel, K Conrad, L Kiper, A Gonzalez, W Musinszki, M Tegtmeier, M Pryde, D Belabed, H Nazare, M De Groot, B Decher, N Fakler, B Carpenter, E Tucker, S Baukrowitz, T A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels |
| title | A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels |
| title_full | A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels |
| title_fullStr | A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels |
| title_full_unstemmed | A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels |
| title_short | A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels |
| title_sort | pharmacological master key mechanism that unlocks the selectivity filter gate in k channels |
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