5DLV
Crystal structure of Autotaxin (ENPP2) with tauroursodeoxycholic acid (TUDCA)
Summary for 5DLV
| Entry DOI | 10.2210/pdb5dlv/pdb |
| Related | 5DLT |
| Descriptor | Ectonucleotide pyrophosphatase/phosphodiesterase family member 2, THIOCYANATE ION, GLYCEROL, ... (12 entities in total) |
| Functional Keywords | autotaxin, enpp2, lpa, steroids, bile salts, tudca, hydrolase |
| Biological source | Rattus norvegicus (Norway Rat) |
| Total number of polymer chains | 2 |
| Total formula weight | 199096.65 |
| Authors | Keune, W.J.,Heidebrecht, T.,von Castelmur, E.,Joosten, R.P.,Perrakis, A. (deposition date: 2015-09-07, release date: 2016-04-13, Last modification date: 2024-11-20) |
| Primary citation | 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 Cited by 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: 27075612DOI: 10.1038/ncomms11248 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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