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Journal Article

Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug

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Ahmed,  Tofayel
Department of Structural Biology, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Tyagi, A., Ahmed, T., Jian, S., Bajaj, S., Ong, S. T., Goay, S. S. M., et al. (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): e2113536119. doi:10.1073/pnas.2113536119.


Cite as: https://hdl.handle.net/21.11116/0000-0009-E1E1-A
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.