5DLT

Crystal structure of Autotaxin (ENPP2) with 7-alpha-hydroxycholesterol

5DLT の概要

• エントリーDOI: 10.2210/pdb5dlt/pdb
• 分子名称: Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, beta-D-mannopyranose-(1-4)-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, lpa, steroids, bile salts, hydrolase
• 由来する生物種: Rattus norvegicus (norway Rat)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 98876.31

構造登録者

Hausmann, J.,Joosten, R.P.,Perrakis, A. (登録日: 2015-09-07, 公開日: 2016-04-13, 最終更新日: 2024-11-13)

主引用文献

Keune, W.J.,Hausmann, J.,Bolier, R.,Tolenaars, D.,Kremer, A.,Heidebrecht, T.,Joosten, R.P.,Sunkara, M.,Morris, A.J.,Matas-Rico, E.,Moolenaar, W.H.,Oude Elferink, R.P.,Perrakis, A.
Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling.
Nat Commun, 7:11248-11248, 2016

PubMed Abstract: Autotaxin (ATX) generates the lipid mediator lysophosphatidic acid (LPA). ATX-LPA signalling is involved in multiple biological and pathophysiological processes, including vasculogenesis, fibrosis, cholestatic pruritus and tumour progression. ATX has a tripartite active site, combining a hydrophilic groove, a hydrophobic lipid-binding pocket and a tunnel of unclear function. We present crystal structures of rat ATX bound to 7α-hydroxycholesterol and the bile salt tauroursodeoxycholate (TUDCA), showing how the tunnel selectively binds steroids. A structure of ATX simultaneously harbouring TUDCA in the tunnel and LPA in the pocket, together with kinetic analysis, reveals that bile salts act as partial non-competitive inhibitors of ATX, thereby attenuating LPA receptor activation. This unexpected interplay between ATX-LPA signalling and select steroids, notably natural bile salts, provides a molecular basis for the emerging association of ATX with disorders associated with increased circulating levels of bile salts. Furthermore, our findings suggest potential clinical implications in the use of steroid drugs.

PubMed: 27075612
DOI: 10.1038/ncomms11248

実験手法

X-RAY DIFFRACTION (1.6 Å)