4QHO

Crystal structure of the human fat mass and obesity associated protein (FTO) in complex with CCO10

4QHO の概要

• エントリーDOI: 10.2210/pdb4qho/pdb
• 関連するPDBエントリー: 3LFM 4IDZ 4IE0 4IE4 4IE5 4IE6 4IE7
• 分子名称: Alpha-ketoglutarate-dependent dioxygenase FTO, ZINC ION, N-{[3-hydroxy-6-(naphthalen-1-yl)pyridin-2-yl]carbonyl}glycine, ... (4 entities in total)
• 機能のキーワード: jelly-roll motif, oxidoreductase, dioxygenase, double-stranded beta helix fold, nucleic acid demethylase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : Q9C0B1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 57210.77

構造登録者

Aik, W.S.,Clunie-O'Connor, C.,McDonough, M.A.,Schofield, C.J. (登録日: 2014-05-28, 公開日: 2015-06-03, 最終更新日: 2023-11-08)

主引用文献

Shishodia, S.,Demetriades, M.,Zhang, D.,Tam, N.Y.,Maheswaran, P.,Clunie-O'Connor, C.,Tumber, A.,Leung, I.K.H.,Ng, Y.M.,Leissing, T.M.,El-Sagheer, A.H.,Salah, E.,Brown, T.,Aik, W.S.,McDonough, M.A.,Schofield, C.J.
Structure-Based Design of Selective Fat Mass and Obesity Associated Protein (FTO) Inhibitors.
J.Med.Chem., 64:16609-16625, 2021

PubMed Abstract: FTO catalyzes the Fe(II) and 2-oxoglutarate (2OG)-dependent modification of nucleic acids, including the demethylation of -methyladenosine (mA) in mRNA. FTO is a proposed target for anti-cancer therapy. Using information from crystal structures of FTO in complex with 2OG and substrate mimics, we designed and synthesized two series of FTO inhibitors, which were characterized by turnover and binding assays, and by X-ray crystallography with FTO and the related bacterial enzyme AlkB. A potent inhibitor employing binding interactions spanning the FTO 2OG and substrate binding sites was identified. Selectivity over other clinically targeted 2OG oxygenases was demonstrated, including with respect to the hypoxia-inducible factor prolyl and asparaginyl hydroxylases (PHD2 and FIH) and selected JmjC histone demethylases (KDMs). The results illustrate how structure-based design can enable the identification of potent and selective 2OG oxygenase inhibitors and will be useful for the development of FTO inhibitors for use .

PubMed: 34762429
DOI: 10.1021/acs.jmedchem.1c01204

実験手法

X-RAY DIFFRACTION (2.37 Å)