A small molecule PTER-selective inhibitor reduces food intake and body weight.

PTER (phosphotriesterase-related) is an amidohydrolase that mediates catabolism of the anorexigenic metabolite N-acetyltaurine. However, the structural basis of PTER ligand binding and catalysis remains unknown, limiting our ability to harness this pathway therapeutically. Here, we solve crystal structures of a eukaryotic PTER in apo and product-bound forms. These structures uncover an unexpected pocket homology between PTER and histone deacetylase (HDAC) enzymes. We exploit this similarity to engineer a substrate-competitive PTER inhibitor called PTERi with nanomolar potency and >100-fold selectivity for PTER over HDACs in vitro. The administration of PTERi to diet-induced obese mice reduces feeding, enhances glucagon-like peptide 1 receptor agonist (GLP1-RA)-induced weight loss, and prevents weight regain after GLP1-RA discontinuation. The structure of PTER connects histone and metabolite deacetylation into a parallel conceptual framework and enables proof-of-concept data for the pharmacological inhibition of PTER in obesity.