Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug
Anu Tyagi, Tofayel Ahmed, Shi Jian, Saumya Bajaj, Seow Theng Ong, Stephanie Shee Min Goay, Yue Zhao, Igor Vorobyov, Changlin Tian, K. George Chandy, Shashi Bhushan
Abstract
Significance Voltage-gated potassium channels (Kv) open with membrane depolarization and allow the flow of K + ions. Ion flow is tightly governed by time-dependent entry into nonconducting inactivated states. Here, we focus on Kv1.3, a channel of physiological importance in immune cells. We used cryogenic electron microscopy to determine structures of human Kv1.3 alone and bound to dalazatide, a peptide inhibitor in human trials. In the unbound state, Kv1.3’s outer pore is rearranged compared to all other K + channels analyzed. Interaction of dalazatide with Kv1.3’s outer pore causes a dynamic rearrangement of the selectivity filter as Kv1.3 enters a drug-blocked state.