RT Journal Article
SR Electronic
T1 Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.19.488765
DO 10.1101/2022.04.19.488765
A1 Purushotham Selvakumar
A1 Ana I. Fernández-Mariño
A1 Nandish Khanra
A1 Changhao He
A1 Alice J. Paquette
A1 Bing Wang
A1 Ruiqi Huang
A1 Vaughn V. Smider
A1 William J. Rice
A1 Kenton J. Swartz
A1 Joel R. Meyerson
YR 2022
UL http://biorxiv.org/content/early/2022/04/19/2022.04.19.488765.abstract
AB The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune response. This role has made the channel a target for therapeutic immunomodulation to block its activity and suppress T cell activation. We determined structures of human Kv1.3 alone, with a nanobody inhibitor, and with an antibody-toxin fusion blocker. Rather than block the channel directly, four copies of the nanobody bind the tetramer’s voltage sensing domains and the pore domain to induce an inactive pore conformation. In contrast, the antibody-toxin fusion docks its toxin domain at the extracellular mouth of the channel to insert a critical lysine into the pore. The lysine induces an active conformation of the pore yet blocks ion permeation. This study visualizes Kv1.3 pore dynamics, defines two distinct mechanisms to suppress Kv1.3 channel activity with exogenous inhibitors, and provides a framework to aid development of emerging T cell immunotherapies.Competing Interest StatementVVS and RH have an equity interest in Minotaur Therapeutics which has a license to the MNT-002 molecule. The authors declare no other competing interests.