Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations.
Potassium (K (+)) channels can regulate ionic conduction through their pore by a mechanism, involving the selectivity filter, known as C-type inactivation. This process is rapid in the hERG K (+) channel and is fundamental to its physiological role. Although mutations within hERG are known to remove...
| Glavni autori: | , , , , , , , , , |
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| Format: | Journal article |
| Jezik: | English |
| Izdano: |
2008
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| _version_ | 1826265904070000640 |
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| author | Stansfeld, P Grottesi, A Sands, Z Sansom, MS Gedeck, P Gosling, M Cox, B Stanfield, P Mitcheson, J Sutcliffe, M |
| author_facet | Stansfeld, P Grottesi, A Sands, Z Sansom, MS Gedeck, P Gosling, M Cox, B Stanfield, P Mitcheson, J Sutcliffe, M |
| author_sort | Stansfeld, P |
| collection | OXFORD |
| description | Potassium (K (+)) channels can regulate ionic conduction through their pore by a mechanism, involving the selectivity filter, known as C-type inactivation. This process is rapid in the hERG K (+) channel and is fundamental to its physiological role. Although mutations within hERG are known to remove this process, a structural basis for the inactivation mechanism has yet to be characterized. Using MD simulations based on homology modeling, we observe that the carbonyl of the filter aromatic, Phe627, forming the S 0 K (+) binding site, swiftly rotates away from the conduction axis in the wild-type channel. In contrast, in well-characterized non-inactivating mutant channels, this conformational change occurs less frequently. In the non-inactivating channels, interactions with a water molecule located behind the selectivity filter are critical to the enhanced stability of the conducting state. We observe comparable conformational changes in the acid sensitive TASK-1 channel and propose a common mechanism in these channels for regulating efflux of K (+) ions through the selectivity filter. |
| first_indexed | 2024-03-06T20:30:53Z |
| format | Journal article |
| id | oxford-uuid:30fefb4c-6a22-49c2-af49-7b246ce768d3 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:30:53Z |
| publishDate | 2008 |
| record_format | dspace |
| spelling | oxford-uuid:30fefb4c-6a22-49c2-af49-7b246ce768d32022-03-26T13:05:08ZInsight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:30fefb4c-6a22-49c2-af49-7b246ce768d3EnglishSymplectic Elements at Oxford2008Stansfeld, PGrottesi, ASands, ZSansom, MSGedeck, PGosling, MCox, BStanfield, PMitcheson, JSutcliffe, MPotassium (K (+)) channels can regulate ionic conduction through their pore by a mechanism, involving the selectivity filter, known as C-type inactivation. This process is rapid in the hERG K (+) channel and is fundamental to its physiological role. Although mutations within hERG are known to remove this process, a structural basis for the inactivation mechanism has yet to be characterized. Using MD simulations based on homology modeling, we observe that the carbonyl of the filter aromatic, Phe627, forming the S 0 K (+) binding site, swiftly rotates away from the conduction axis in the wild-type channel. In contrast, in well-characterized non-inactivating mutant channels, this conformational change occurs less frequently. In the non-inactivating channels, interactions with a water molecule located behind the selectivity filter are critical to the enhanced stability of the conducting state. We observe comparable conformational changes in the acid sensitive TASK-1 channel and propose a common mechanism in these channels for regulating efflux of K (+) ions through the selectivity filter. |
| spellingShingle | Stansfeld, P Grottesi, A Sands, Z Sansom, MS Gedeck, P Gosling, M Cox, B Stanfield, P Mitcheson, J Sutcliffe, M Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations. |
| title | Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations. |
| title_full | Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations. |
| title_fullStr | Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations. |
| title_full_unstemmed | Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations. |
| title_short | Insight into the mechanism of inactivation and pH sensitivity in potassium channels from molecular dynamics simulations. |
| title_sort | insight into the mechanism of inactivation and ph sensitivity in potassium channels from molecular dynamics simulations |
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