Structurally defining neurokinin selectivity to improve NK2R agonists

Incretin-based obesity pharmacotherapies have revolutionized patient care but act predominantly by reducing food intake. Approaches that increase energy expenditure could improve efficacy but remain challenging to harness. Recently, neurokinin 2 receptor (NK2R) activation was shown to both lower food intake and stimulate energy expenditure in preclinical models. However, the endogenous NK2R ligand, NKA, crossreacts with other receptor family members that are linked to unwanted adverse effects. Therefore, understanding NK2R selectivity is the key to unlocking its therapeutic potential. Here we generated cryo-electron microscopy complexes of NK2R bound to NKA and several synthetic agonists to discover candidate interactions driving selectivity. Targeted receptor and ligand mutagenesis was then used to functionally validate the specific residues in the NK2R binding pocket and the C terminus of synthetic peptide agonists that were responsible for selectivity. These findings provide a structural framework for defining neurokinin selectivity and enable the development of improved NK2R agonists for clinical investigation.