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https://hdl.handle.net/10356/162571
Title: | Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug | Authors: | 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 |
Keywords: | Science::Biological sciences | Issue Date: | 2022 | Source: | Tyagi, A., Ahmed, T., Jian, S., Bajaj, S., Ong, S. T., Goay, S. S. M., Zhao, Y., Vorobyov, I., Tian, C., Chandy, K. G. & Bhushan, S. (2022). Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug. Proceedings of the National Academy of Sciences of the United States of America, 119(5). https://dx.doi.org/10.1073/pnas.2113536119 | Project: | MOE2017-T2-2-089 MOE2020-T1-002-059 MOE2016-T2-2-032 |
Journal: | Proceedings of the National Academy of Sciences of the United States of America | Abstract: | 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. | URI: | https://hdl.handle.net/10356/162571 | ISSN: | 0027-8424 | DOI: | 10.1073/pnas.2113536119 | Schools: | School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) |
Research Centres: | Nanyang Institute of Structural Biology | Rights: | © The Authors. This article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND). | Fulltext Permission: | open | Fulltext Availability: | With Fulltext |
Appears in Collections: | LKCMedicine Journal Articles SBS Journal Articles |
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