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

• Main 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
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2022
• Subjects: Science::Biological sciences; Ion Channels; Potassium Channels
• Online Access: https://hdl.handle.net/10356/162571
• Institution: Nanyang Technological University

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.