Cryo-EM structures reveal that a nanobody inhibitor induces an inactive pore conformation by binding the voltage sensing and pore domains, while an antibody-toxin fusion blocks ion permeation by inserting a lysine into the pore.
This structural study defines two distinct mechanisms of Kv1.3 channel inhibition, providing a framework for developing T cell immunotherapies.
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.
Selvakumar et al. (Mon,) reported a other. Nanobody A0194009G09 and MNT-002 (antibody-ShK fusion) vs. Unbound Kv1.3 channel was evaluated on Cryo-EM structure determination and channel inhibition mechanisms. Cryo-EM structures reveal that a nanobody inhibitor induces an inactive pore conformation by binding the voltage sensing and pore domains, while an antibody-toxin fusion blocks ion permeation by inserting a lysine into the pore.