PT  - JOURNAL ARTICLE
AU  - Adam J Stein
AU  - Gretchen Bain
AU  - Pat Prodanovich
AU  - Angelina M Santini
AU  - Janice Darlington
AU  - Nina M.P. Stelzer
AU  - Ranjinder S Sidhu
AU  - Jeffrey Schaub
AU  - Lance Goulet
AU  - Dave Lonergan
AU  - Imelda Calderon
AU  - Jilly F Evans
AU  - John H Hutchinson
TI  - Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding
AID  - 10.1124/mol.115.100404
DP  - 2015 Jan 01
TA  - Molecular Pharmacology
PG  - mol.115.100404
4099  - http://molpharm.aspetjournals.org/content/early/2015/09/14/mol.115.100404.short
4100  - http://molpharm.aspetjournals.org/content/early/2015/09/14/mol.115.100404.full
AB  - Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine (LPC) 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 Here we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors.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.