Filter flexibility in a mammalian K channel: models and simulations of Kir6.2 mutants.
The single-channel conductance varies significantly between different members of the inward rectifier (Kir) family of potassium channels. Mutations at three sites in Kir6.2 have been shown to produce channels with reduced single-channel conductance, the largest reduction (to 40% of wild-type) being...
| Príomhchruthaitheoirí: | , , , |
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| Formáid: | Journal article |
| Teanga: | English |
| Foilsithe / Cruthaithe: |
2003
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| _version_ | 1826292716955238400 |
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| author | Capener, C Proks, P Ashcroft, F Sansom, MS |
| author_facet | Capener, C Proks, P Ashcroft, F Sansom, MS |
| author_sort | Capener, C |
| collection | OXFORD |
| description | The single-channel conductance varies significantly between different members of the inward rectifier (Kir) family of potassium channels. Mutations at three sites in Kir6.2 have been shown to produce channels with reduced single-channel conductance, the largest reduction (to 40% of wild-type) being for V127T. We have used homology modeling (based on a KcsA template) combined with molecular dynamics simulations in a phosphatidycholine bilayer to explore whether changes in structural dynamics of the filter were induced by three such mutations: V127T, M137C, and G135F. Overall, 12 simulations of Kir6.2 models, corresponding to a total simulation time of 27 ns, have been performed. In these simulations we focused on distortions of the selectivity filter, and on the presence/absence of water molecules lying behind the filter, which form interactions with the filter and the remainder of the protein. Relative to the wild-type simulation, the V127T mutant showed significant distortion of the filter such that approximately 50% of the simulation time was spent in a closed conformation. While in this conformation, translocation of K(+) ions between sites S1 and S2 was blocked. The distorted filter conformation resembles that of the bacterial channel KcsA when crystallized in the presence of a low [K(+)]. This suggests filter distortion may be a possible general model for determining the conductance of K channels. |
| first_indexed | 2024-03-07T03:19:00Z |
| format | Journal article |
| id | oxford-uuid:b6caccd5-f0c5-4011-a1b4-1c295adf1d2b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:19:00Z |
| publishDate | 2003 |
| record_format | dspace |
| spelling | oxford-uuid:b6caccd5-f0c5-4011-a1b4-1c295adf1d2b2022-03-27T04:43:33ZFilter flexibility in a mammalian K channel: models and simulations of Kir6.2 mutants.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b6caccd5-f0c5-4011-a1b4-1c295adf1d2bEnglishSymplectic Elements at Oxford2003Capener, CProks, PAshcroft, FSansom, MSThe single-channel conductance varies significantly between different members of the inward rectifier (Kir) family of potassium channels. Mutations at three sites in Kir6.2 have been shown to produce channels with reduced single-channel conductance, the largest reduction (to 40% of wild-type) being for V127T. We have used homology modeling (based on a KcsA template) combined with molecular dynamics simulations in a phosphatidycholine bilayer to explore whether changes in structural dynamics of the filter were induced by three such mutations: V127T, M137C, and G135F. Overall, 12 simulations of Kir6.2 models, corresponding to a total simulation time of 27 ns, have been performed. In these simulations we focused on distortions of the selectivity filter, and on the presence/absence of water molecules lying behind the filter, which form interactions with the filter and the remainder of the protein. Relative to the wild-type simulation, the V127T mutant showed significant distortion of the filter such that approximately 50% of the simulation time was spent in a closed conformation. While in this conformation, translocation of K(+) ions between sites S1 and S2 was blocked. The distorted filter conformation resembles that of the bacterial channel KcsA when crystallized in the presence of a low [K(+)]. This suggests filter distortion may be a possible general model for determining the conductance of K channels. |
| spellingShingle | Capener, C Proks, P Ashcroft, F Sansom, MS Filter flexibility in a mammalian K channel: models and simulations of Kir6.2 mutants. |
| title | Filter flexibility in a mammalian K channel: models and simulations of Kir6.2 mutants. |
| title_full | Filter flexibility in a mammalian K channel: models and simulations of Kir6.2 mutants. |
| title_fullStr | Filter flexibility in a mammalian K channel: models and simulations of Kir6.2 mutants. |
| title_full_unstemmed | Filter flexibility in a mammalian K channel: models and simulations of Kir6.2 mutants. |
| title_short | Filter flexibility in a mammalian K channel: models and simulations of Kir6.2 mutants. |
| title_sort | filter flexibility in a mammalian k channel models and simulations of kir6 2 mutants |
| work_keys_str_mv | AT capenerc filterflexibilityinamammaliankchannelmodelsandsimulationsofkir62mutants AT proksp filterflexibilityinamammaliankchannelmodelsandsimulationsofkir62mutants AT ashcroftf filterflexibilityinamammaliankchannelmodelsandsimulationsofkir62mutants AT sansomms filterflexibilityinamammaliankchannelmodelsandsimulationsofkir62mutants |