Structure of Lymphocyte Potassium Channel K v1.3 and Modulation by Cell Penetrating Immunomodulatory Plant Defensin

Here, we report the cryo-electron microscopy structure of the human voltage-gated hK v 1.3 potassium channel in T lymphocytes in complex with its accessory protein K v β2 at 3.4 Å resolution. We also describe EgK5, a designed peptide-analogue of plant defensins from grapevine and oil palm, that modulates hK v 1.3/K v β2 by a distinctive mechanism. EgK5 enters cells and binds to the channel near its inner pore and also to K v β2. This interaction elevates flexibility and induces conformational changes in the hK v 1.3/K v β2 complex, resulting in the suppression of hK v 1.3 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.