Abstract
<title>Abstract</title> <p>KV1.3 is a validated autoimmune drug target, yet all disclosed inhibitors converge on a narrow set of conserved binding sites, suffering from poor selectivity or clinical failure. Whether KV1.3 harbors a distinctive, druggable pocket amenable to selective targeting has remained elusive. Here we identify a previously uncharacterized extracellular allosteric pocket in KV1.3 through functional and structural characterization of MPiN, a highly selective, state-dependent inhibitor with in vivo efficacy in a mouse psoriasis model. Formed by the PP1–PP2 turret loops, the pore helix, and the extracellular ends of the S5 and S6 helices, this pocket mediates channel inhibition through a bidirectional pore-to-sensor coupling that simultaneously constricts the selectivity filter and facilitates voltage-sensor activation. Unexpectedly, despite the extensive structural conservation of this pocket across KV1 paralogs, subtype selectivity is dictated by the peripheral residues G427 and H451, which define pocket geometry without directly contacting the ligand, thereby establishing a geometry-driven “non-contact selectivity” mechanism. By opening a previously unrecognized and structurally distinct chemical space on KV1.3 and redefining how subtype selectivity is achieved within a conserved channel family, this work lays the structural and conceptual foundation for the rational, structure-guided design of next-generation KV1.3-targeting immunomodulators.</p>