4ZG7

Structural basis for inhibition of human autotaxin by four novel compounds

4ZG7 の概要

• エントリーDOI: 10.2210/pdb4zg7/pdb
• 関連するPDBエントリー: 4ZG6 4ZG9 4ZGA
• 分子名称: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (10 entities in total)
• 機能のキーワード: autotaxin, enpp2, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Secreted : Q13822
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 95007.22

構造登録者

Stein, A.J.,Bain, G.,Hutchinson, J.H.,Evans, J.F. (登録日: 2015-04-22, 公開日: 2015-10-14, 最終更新日: 2024-10-23)

主引用文献

Stein, A.J.,Bain, G.,Prodanovich, P.,Santini, A.M.,Darlington, J.,Stelzer, N.M.,Sidhu, R.S.,Schaub, J.,Goulet, L.,Lonergan, D.,Calderon, I.,Evans, J.F.,Hutchinson, J.H.
Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding.
Mol.Pharmacol., 88:982-992, 2015

PubMed Abstract: Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is a bioactive phospholipid that regulates diverse biological processes, including cell proliferation, migration, and survival/apoptosis, through the activation of a family of G protein-coupled receptors. The ATX-LPA pathway has been implicated in many pathologic conditions, including cancer, fibrosis, inflammation, cholestatic pruritus, and pain. Therefore, ATX inhibitors represent an attractive strategy for the development of therapeutics to treat a variety of diseases. Mouse and rat ATX have been crystallized previously with LPA or small-molecule inhibitors bound. Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors. We demonstrate that the mechanism of inhibition of each compound reflects its unique interactions with human ATX. Our studies may provide a basis for the rational design of novel ATX inhibitors.

PubMed: 26371182
DOI: 10.1124/mol.115.100404

実験手法

X-RAY DIFFRACTION (1.75 Å)