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Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug
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Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug
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Journal Article
Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug
2022
Overview
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.
Publisher
National Academy of Sciences
Subject
Amino Acid Sequence - genetics
/ Binding
/ Channels
/ Humans
/ Ion Channel Gating - physiology
/ Ions
/ Kv1.3 Potassium Channel - drug effects
/ Kv1.3 Potassium Channel - metabolism
/ Kv1.3 Potassium Channel - ultrastructure
/ Microscopy, Electron - methods
/ Potassium channels (voltage-gated)
/ Potassium Channels - metabolism
/ Potassium Channels - ultrastructure
/ Potassium Channels, Voltage-Gated - metabolism
/ Potassium Channels, Voltage-Gated - ultrastructure
