Open AccessRearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug
Author(s) -
Anu Tyagi,
Tofayel Ahmed,
Jing Shi,
Saumya Bajaj,
Seow Theng Ong,
Stephanie Shee Min Goay,
Yue Zhao,
Igor Vorobyov,
Changlin Tian,
K. George Chandy,
Shashi Bhushan
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2113536119
Subject(s) - selectivity , chemistry , hydrogen bond , potassium channel , stereochemistry , biophysics , voltage gated potassium channel , binding site , ion channel , crystallography , biochemistry , molecule , biology , receptor , catalysis , organic chemistry
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.