Key result
Nanobody and antibody-toxin inhibitors suppress human Kv1.3 channels via distinct pore-inactivating and permeation-blocking mechanisms.
Why the study?
The Kv1.3 potassium channel on activated T cells is a target for immunomodulation to suppress T cell activation, but structural mechanisms of inhibition were unclear.
Visualizes Kv1.3 pore dynamics and defines two distinct mechanisms of exogenous inhibitors, providing a structural 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. 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.
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Selvakumar et al. (2022) studied Kv1.3 channel modulation. A0194009G09 nanobody and MNT-002 antibody-ShK fusion vs. Unbound Kv1.3 was evaluated on Cryo-EM structure resolution and conformational changes. Cryo-EM structures of human Kv1.3 revealed that a nanobody inhibitor induces an inactive pore conformation, whereas an antibody-toxin fusion blocks ion permeation by inserting a lysine into the pore.
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