Press Releases
Jan. 17, 2011

Structure of a protein associated with cancer metastasis

Presenters
  • Osamu Nureki (Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo)
  • Junken Aoki (Graduate School of Pharmaceutical Sciences, Tohoku University)
  • Junichi Takagi (Institute for Protein Research, Osaka University)
  • Hiroshi Nishimasu (Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo)

Abstract

Autotaxin (ATX) is a secreted lysophospholipase D that produces lysophosphatidic acid (LPA), a lipid mediator that activates G protein-coupled receptors (GPCRs) to evoke a wide range of cellular responses. ATX is essential for normal development and is implicated in a number of physiological processes, such as blood vessel formation, as well as in pathophysiological conditions, such as wound healing and neuropathic pain. In addition, aberrant ATX expression is associated with various human diseases, such as cancer, arteriosclerosis and lung fibrosis. ATX thus is thought to be an attractive target for new drugs. Here, we solved the 3D structures of mouse ATX alone and in complex with LPAs having different acyl-chain lengths and saturations. These structures reveal the molecular mechanism by which ATX generates and delivers LPAs. Furthermore, our high-resolution structures provide the basis for the rational design of effective ATX inhibitors that could serve as new anticancer drugs.

Paper information

Hiroshi Nishimasu, Shinichi Okudaira, Kotaro Hama, Emiko Mihara, Naoshi Dohmae, Asuka Inoue, Ryuichiro Ishitani, Junichi Takagi, Junken Aoki & Osamu Nureki, Crystal structure of autotaxin and insight into GPCR activation by lipid mediators, Nature Structural & Molecular Biology, Published online 17 January 2011.

Figure 1

Figure 1. ATX-LPA signaling pathway.

Figure 2

Figure 2. 3D structure of the ATX-14:0-LPA complex.

Figure 3

Figure 3. Hydrophobic pocket that accommodates LPA molecules.

Figure 4

Figure 4. Hydrophobic channel that could deliver LPAs to specific GPCRs.