Structural highlights
Publication Abstract from PubMedPTER (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. A small molecule PTER-selective inhibitor reduces food intake and body weight.,Fu S, Wang L, Li VL, Lyu X, Wei W, Shi X, Deng S, Barber JL, Tahir UA, Adams C, Carson A, Hidalgo B, Raffield LM, Wilson JG, Razumkov H, Xiao S, Spaas J, Fernandez D, Zhang T, Gerszten RE, Benson MD, Gray NS, Hinshaw SM, Long JZ bioRxiv [Preprint]. 2026 Jan 28:2026.01.26.701829. doi: , 10.64898/2026.01.26.701829. PMID:41659642[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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