An allosteric pocket in KV1.3 defines a distinct chemical space for immunomodulator design

Abstract

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 unknown. Here we report MPiN, a highly selective, state-dependent KV1.3 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 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 an unrecognized, structurally distinct chemical space on KV1.3 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 KV1.3 immunomodulators.