9EFB

Chemical inhibition of the N-acetyltaurine amidohydrolase PTER reduces food intake and obesity

9EFB の概要

• エントリーDOI: 10.2210/pdb9efb/pdb
• 分子名称: Phosphotriesterase-related protein, 2-AMINOETHANESULFONIC ACID, ACETATE ION, ... (5 entities in total)
• 機能のキーワード: n-acetyltaurine amidohydrolase, hydrolase
• 由来する生物種: Amphimedon queenslandica
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 78921.81

構造登録者

Fu, S.,Hinshaw, S.M. (登録日: 2024-11-20, 公開日: 2026-02-25)

主引用文献

Fu, S.,Wang, L.,Li, V.L.,Lyu, X.,Wei, W.,Shi, X.,Deng, S.,Barber, J.L.,Tahir, U.A.,Adams, C.,Carson, A.,Hidalgo, B.,Raffield, L.M.,Wilson, J.G.,Razumkov, H.,Xiao, S.,Spaas, J.,Fernandez, D.,Zhang, T.,Gerszten, R.E.,Benson, M.D.,Gray, N.S.,Hinshaw, S.M.,Long, J.Z.
A small molecule PTER-selective inhibitor reduces food intake and body weight.
Biorxiv, 2026

PubMed 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.

PubMed: 41659642
DOI: 10.64898/2026.01.26.701829

実験手法

X-RAY DIFFRACTION (2.4 Å)