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Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug
We report two structures of the human voltage-gated potassium channel (Kv) Kv1.3 in immune cells alone (apo-Kv1.3) and bound to an immunomodulatory drug called dalazatide (dalazatide–Kv1.3). Both the apo-Kv1.3 and dalazatide–Kv1.3 structures are in an activated state based on their depolarized volta...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8812516/ https://www.ncbi.nlm.nih.gov/pubmed/35091471 http://dx.doi.org/10.1073/pnas.2113536119 |
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author | Tyagi, Anu Ahmed, Tofayel Jian, Shi Bajaj, Saumya Ong, Seow Theng Goay, Stephanie Shee Min Zhao, Yue Vorobyov, Igor Tian, Changlin Chandy, K. George Bhushan, Shashi |
author_facet | Tyagi, Anu Ahmed, Tofayel Jian, Shi Bajaj, Saumya Ong, Seow Theng Goay, Stephanie Shee Min Zhao, Yue Vorobyov, Igor Tian, Changlin Chandy, K. George Bhushan, Shashi |
author_sort | Tyagi, Anu |
collection | PubMed |
description | We report two structures of the human voltage-gated potassium channel (Kv) Kv1.3 in immune cells alone (apo-Kv1.3) and bound to an immunomodulatory drug called dalazatide (dalazatide–Kv1.3). Both the apo-Kv1.3 and dalazatide–Kv1.3 structures are in an activated state based on their depolarized voltage sensor and open inner gate. In apo-Kv1.3, the aromatic residue in the signature sequence (Y447) adopts a position that diverges 11 Å from other K(+) channels. The outer pore is significantly rearranged, causing widening of the selectivity filter and perturbation of ion binding within the filter. This conformation is stabilized by a network of intrasubunit hydrogen bonds. In dalazatide–Kv1.3, binding of dalazatide to the channel’s outer vestibule narrows the selectivity filter, Y447 occupies a position seen in other K(+) channels, and this conformation is stabilized by a network of intersubunit hydrogen bonds. These remarkable rearrangements in the selectivity filter underlie Kv1.3’s transition into the drug-blocked state. |
format | Online Article Text |
id | pubmed-8812516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-88125162022-07-28 Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug Tyagi, Anu Ahmed, Tofayel Jian, Shi Bajaj, Saumya Ong, Seow Theng Goay, Stephanie Shee Min Zhao, Yue Vorobyov, Igor Tian, Changlin Chandy, K. George Bhushan, Shashi Proc Natl Acad Sci U S A Biological Sciences We report two structures of the human voltage-gated potassium channel (Kv) Kv1.3 in immune cells alone (apo-Kv1.3) and bound to an immunomodulatory drug called dalazatide (dalazatide–Kv1.3). Both the apo-Kv1.3 and dalazatide–Kv1.3 structures are in an activated state based on their depolarized voltage sensor and open inner gate. In apo-Kv1.3, the aromatic residue in the signature sequence (Y447) adopts a position that diverges 11 Å from other K(+) channels. The outer pore is significantly rearranged, causing widening of the selectivity filter and perturbation of ion binding within the filter. This conformation is stabilized by a network of intrasubunit hydrogen bonds. In dalazatide–Kv1.3, binding of dalazatide to the channel’s outer vestibule narrows the selectivity filter, Y447 occupies a position seen in other K(+) channels, and this conformation is stabilized by a network of intersubunit hydrogen bonds. These remarkable rearrangements in the selectivity filter underlie Kv1.3’s transition into the drug-blocked state. National Academy of Sciences 2022-01-28 2022-02-01 /pmc/articles/PMC8812516/ /pubmed/35091471 http://dx.doi.org/10.1073/pnas.2113536119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Tyagi, Anu Ahmed, Tofayel Jian, Shi Bajaj, Saumya Ong, Seow Theng Goay, Stephanie Shee Min Zhao, Yue Vorobyov, Igor Tian, Changlin Chandy, K. George Bhushan, Shashi Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug |
title | Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug |
title_full | Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug |
title_fullStr | Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug |
title_full_unstemmed | Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug |
title_short | Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug |
title_sort | rearrangement of a unique kv1.3 selectivity filter conformation upon binding of a drug |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8812516/ https://www.ncbi.nlm.nih.gov/pubmed/35091471 http://dx.doi.org/10.1073/pnas.2113536119 |
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