An allosteric pocket in K _V 1.3 defines a distinct chemical space for immunomodulator design

K _V 1.3 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 K _V 1.3 harbors a distinctive, druggable pocket amenable to selective targeting has remained unknown. Here we report MPiN, a highly selective, state-dependent K _V 1.3 inhibitor with in vivo efficacy in a mouse psoriasis model, which engages a previously uncharacterized extracellular allosteric pocket framed by the PP1-PP2 turret loops, the pore helix and the outer S5/S6 helices, acting through a bidirectional pore-to-sensor coupling that simultaneously constricts the selectivity filter and facilitates the voltage sensor toward activation. Unexpectedly, despite the extensive structural conservation of this pocket across K _V 1 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 an unrecognized, structurally distinct chemical space on K _V 1.3 and redefining how selectivity is achieved within a conserved channel family, this work lays the structural and conceptual foundation for rational, structure-guided design of next-generation K _V 1.3 immunomodulators.