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 Here, we present the crystal structures of human ATX in complex with four previously unpublished, structurally distinct ATX inhibitors.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.
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Stein
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.) gbain@pharmakea.com.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Bain
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Pat
authors.initials: P
authors.lastname: Prodanovich
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Angelina M
authors.initials: AM
authors.lastname: Santini
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Janice
authors.initials: J
authors.lastname: Darlington
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Nina M P
authors.initials: NM
authors.lastname: Stelzer
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Ranjinder S
authors.initials: RS
authors.lastname: Sidhu
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schaub
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Lance
authors.initials: L
authors.lastname: Goulet
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Dave
authors.initials: D
authors.lastname: Lonergan
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Imelda
authors.initials: I
authors.lastname: Calderon
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: Jilly F
authors.initials: JF
authors.lastname: Evans
authors.affiliation: Cayman Chemical Company, Ann Arbor, Michigan (A.J.S., N.M.P.S., R.S.S., J.S.); and PharmAkea, San Diego, California (G.B., P.P., A.M.S., J.D., L.G., D.L., I.C., J.F.E., J.H.H.).
authors.forename: John H
authors.initials: JH
authors.lastname: Hutchinson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003460:Crystallization; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D000099189:Lysophospholipase D
chemical_list: D004791:Enzyme Inhibitors; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D