A small molecule PTER-selective inhibitor reduces food intake and body weight
Fu, S.; Wang, L.; Li, V. L.; Lyu, X.; Wei, W.; Shi, X.; Deng, S.; Barber, J.; Tahir, U.; Adams, C.; Carson, A.; Hidalgo, B. A.; Raffield, L. M.; Wilson, J. G.; Razumkov, H.; Xiao, S.; Spaas, J.; Fernandez, D.; Zhang, T.; Gerszten, R. E.; Benson, M.; Gray, N.; Hinshaw, S. M.; Long, J. Z.
Show abstract
PTER (phosphotriesterase-related) is an amidohydrolase that mediates catabolism of the anorexigenic taurine metabolite N-acetyltaurine. However, the structural basis of PTER ligand binding and catalysis remain 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 first-in-class substrate-competitive PTER inhibitor called PTERi with nanomolar potency and >100-fold selectivity for PTER over HDACs in vitro. Administration of PTERi to diet-induced obese mice reduces feeding, enhances GLP1-RA (glucagon like peptide 1 receptor agonist)-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 pharmacological inhibition of PTER in obesity.
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