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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).
Project: MOE2017-T2-2-089
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.
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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