Structural basis for specific inhibition of Autotaxin by a DNA aptamer

Kazuki Kato, Hisako Ikeda, Shin Miyakawa, Satoshi Futakawa, Yosuke Nonaka, Masatoshi Fujiwara, Shinichi Okudaira, Kuniyuki Kano, Junken Aoki, Junko Morita, Ryuichiro Ishitani, Hiroshi Nishimasu, Yoshikazu Nakamura, Osamu Nureki

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32 Citations (Scopus)

Abstract

ATX is a plasma lysophospholipase D that hydrolyzes lysophosphatidylcholine (LPC) and produces lysophosphatidic acid. To date, no ATX-inhibition-mediated treatment strategies for human diseases have been established. Here, we report anti-ATX DNA aptamers that inhibit ATX with high specificity and efficacy. We solved the crystal structure of ATX in complex with the anti-ATX aptamer RB011, at 2.0-Å resolution. RB011 binds in the vicinity of the active site through base-specific interactions, thus preventing the access of the choline moiety of LPC substrates. Using the structural information, we developed the modified anti-ATX DNA aptamer RB014, which exhibited in vivo efficacy in a bleomycin-induced pulmonary fibrosis mouse model. Our findings reveal the structural basis for the specific inhibition of ATX by the anti-ATX aptamer and highlight the therapeutic potential of anti-ATX aptamers for the treatment of human diseases, such as pulmonary fibrosis.

Original languageEnglish
JournalNature Structural and Molecular Biology
DOIs
Publication statusAccepted/In press - 2016 Apr 4

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Kato, K., Ikeda, H., Miyakawa, S., Futakawa, S., Nonaka, Y., Fujiwara, M., Okudaira, S., Kano, K., Aoki, J., Morita, J., Ishitani, R., Nishimasu, H., Nakamura, Y., & Nureki, O. (Accepted/In press). Structural basis for specific inhibition of Autotaxin by a DNA aptamer. Nature Structural and Molecular Biology. https://doi.org/10.1038/nsmb.3200