Title : Structural Basis for Inhibition of
Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding
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- Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors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