Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators

Purushotham Selvakumar, Ana I. Fernández-Mariño, Nandish Khanra, Changhao He, Alice J. Paquette, Bing Wang, Ruiqi Huang, Vaughn V. Smider, William J. Rice, Kenton J. Swartz and Joel R. Meyerson ()
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Purushotham Selvakumar: Weill Cornell Medical College
Ana I. Fernández-Mariño: National Institutes of Health
Nandish Khanra: Weill Cornell Medical College
Changhao He: Weill Cornell Medical College
Alice J. Paquette: New York University School of Medicine
Bing Wang: New York University School of Medicine
Ruiqi Huang: Applied Biomedical Science Institute
Vaughn V. Smider: Applied Biomedical Science Institute
William J. Rice: New York University School of Medicine
Kenton J. Swartz: National Institutes of Health
Joel R. Meyerson: Weill Cornell Medical College

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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. Here, we report 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 stabilizes 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.

Date: 2022
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DOI: 10.1038/s41467-022-31285-5

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