Publications

• Crystal structure of autotaxin and insight into GPCR activation by lipid mediators.

  Nishimasu H., Okudaira S., Hama K., Mihara E., Dohmae N., Inoue A., Ishitani R., Takagi J., Aoki J., Nureki O.

  Autotaxin (ATX, also known as Enpp2) is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine to generate lysophosphatidic acid (LPA), a lipid mediator that activates G protein-coupled receptors to evoke various cellular responses. Here, we report the crystal structures of mouse A ... >> More

  Autotaxin (ATX, also known as Enpp2) is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine to generate lysophosphatidic acid (LPA), a lipid mediator that activates G protein-coupled receptors to evoke various cellular responses. Here, we report the crystal structures of mouse ATX alone and in complex with LPAs with different acyl-chain lengths and saturations. These structures reveal that the multidomain architecture helps to maintain the structural rigidity of the lipid-binding pocket, which accommodates the respective LPA molecules in distinct conformations. They indicate that a loop region in the catalytic domain is a major determinant for the substrate specificity of the Enpp family enzymes. Furthermore, along with biochemical and biological data, these structures suggest that the produced LPAs are delivered from the active site to cognate G protein-coupled receptors through a hydrophobic channel. << Less

  Nat. Struct. Mol. Biol. 18:205-212(2011) [PubMed] [EuropePMC]

• Screening and X-ray crystal structure-based optimization of autotaxin (ENPP2) inhibitors, using a newly developed fluorescence probe.

  Kawaguchi M., Okabe T., Okudaira S., Nishimasu H., Ishitani R., Kojima H., Nureki O., Aoki J., Nagano T.

  Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), was originally identified as a tumor cell autocrine motility factor and was found to be identical to plasma lysophospholipase D, which is the predominant contributor to lysophosphatidic acid (LPA) production ... >> More

  Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), was originally identified as a tumor cell autocrine motility factor and was found to be identical to plasma lysophospholipase D, which is the predominant contributor to lysophosphatidic acid (LPA) production from lysophospholipids. ATX is therefore considered to regulate the physiological and pathological roles of LPA, including angiogenesis, lymphocyte trafficking, tissue fibrosis, and cancer cell invasion and metastasis. Thus, it is a potential therapeutic target. Here, we first developed a sensitive and specific ATX fluorescence probe, TG-mTMP, and used it to screen ATX inhibitors in a large chemical library. This probe, which is superior to previously available probes FS-3 and CPF4 in terms of sensitivity or specificity, enabled us to identify several novel ATX inhibitor scaffolds. We solved the crystal structures of ATX complexes with the hit compounds at high resolution (1.75-1.95 Å) and used this information to guide optimization of the structure of a selected inhibitor. The optimized compounds, 3BoA and its derivatives, exhibited potent ATX-inhibitory activity both in vitro and in vivo. These inhibitors are expected to be useful tools to understand the roles of ATX in vitro and in vivo and may also be candidate anti-ATX therapeutic agents. << Less

  ACS Chem. Biol. 8:1713-1721(2013) [PubMed] [EuropePMC]

• A lysophospholipase D pathway in the metabolism of ether-linked lipids in brain microsomes.

  Wykle R.L., Schremmer J.M.

  J Biol Chem 249:1742-1746(1974) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• Structural basis of substrate discrimination and integrin binding by autotaxin.

  Hausmann J., Kamtekar S., Christodoulou E., Day J.E., Wu T., Fulkerson Z., Albers H.M., van Meeteren L.A., Houben A.J., van Zeijl L., Jansen S., Andries M., Hall T., Pegg L.E., Benson T.E., Kasiem M., Harlos K., Kooi C.W., Smyth S.S., Ovaa H., Bollen M., Morris A.J., Moolenaar W.H., Perrakis A.

  Autotaxin (ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase-2, ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemoattractant for many cell types. ATX-LPA signaling is involved in various pathologies includin ... >> More

  Autotaxin (ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase-2, ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemoattractant for many cell types. ATX-LPA signaling is involved in various pathologies including tumor progression and inflammation. However, the molecular basis of substrate recognition and catalysis by ATX and the mechanism by which it interacts with target cells are unclear. Here, we present the crystal structure of ATX, alone and in complex with a small-molecule inhibitor. We have identified a hydrophobic lipid-binding pocket and mapped key residues for catalysis and selection between nucleotide and phospholipid substrates. We have shown that ATX interacts with cell-surface integrins through its N-terminal somatomedin B-like domains, using an atypical mechanism. Our results define determinants of substrate discrimination by the ENPP family, suggest how ATX promotes localized LPA signaling and suggest new approaches for targeting ATX with small-molecule therapeutic agents. << Less

  Nat. Struct. Mol. Biol. 18:198-204(2011) [PubMed] [EuropePMC]

  This publication is cited by 5 other entries.

• Studies of lysophospholipase D of rat liver and other tissues.

  Wykle R.L., Kraemer W.F., Schremmer J.M.

  Arch Biochem Biophys 184:149-155(1977) [PubMed] [EuropePMC]

  This publication is cited by 1 other entry.