Structure of Lymphocyte Potassium Channel K v 1.3 and Modulation by Cell-Penetrating Immunomodulatory Plant Defensin

Here, we report the cryo-electron microscopy structure of the human voltage-gated hKv1.3 potassium channel in T lymphocytes in complex with its accessory protein Kvβ2 at 3.4A resolution. We also describe EgK5, a designed peptide-analogue of plant defensins from grapevine and oil palm, that modulates hKv1.3/Kvβ2 by a distinctive mechanism. EgK5 enters cells and binds to the channel near its inner pore and also to Kvβ2. This interaction elevates flexibility and induces conformational changes in the hKv1.3/Kvβ2 complex, resulting in the suppression of hKv1.3 currents. EgK5 inhibits the proliferation of effector memory T cells, a subset enriched amongst pathogenic autoreactive T cells in autoimmune diseases, and treats disease in rat models of rheumatoid arthritis and atopic dermatitis with no signs of toxicity at 10-100 times the in vivo dose. We provide a framework for the structure-guided discovery of drugs that modulate channel activity by intracellular binding and conductance-reduction.