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.

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We thank the beamline staff at BL32XU and BL41XU of SPring-8, Japan, for assistance with data collection. We thank T. Kishimoto for the LPA assays, S. Yamazaki for in vitro assays, E. Inomata for aptamer stability experiments and all other Ribomic members for discussions. We thank T. Nagano (University of Tokyo) for 3BoA. This work was supported by a grant from the Core Research for Evolutional Science and Technology Program, the Creation of Basic Chronic Inflammation, from the Japan Science and Technology Agency, to O.N. This work was also supported in part by a grant from NEDO.

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Author notes

    • Kazuki Kato
    •  & Hisako Ikeda

    These authors contributed equally to this work.


  1. Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan.

    • Kazuki Kato
    • , Junko Morita
    • , Ryuichiro Ishitani
    • , Hiroshi Nishimasu
    •  & Osamu Nureki
  2. Ribomic Inc., Tokyo, Japan.

    • Hisako Ikeda
    • , Shin Miyakawa
    • , Satoshi Futakawa
    • , Yosuke Nonaka
    • , Masatoshi Fujiwara
    •  & Yoshikazu Nakamura
  3. Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.

    • Shinichi Okudaira
    • , Kuniyuki Kano
    •  & Junken Aoki
  4. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Tokyo, Japan.

    • Hiroshi Nishimasu
  5. Institute of Medical Science, University of Tokyo, Tokyo, Japan.

    • Yoshikazu Nakamura


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K. Kato prepared and crystallized the protein and determined the crystal structure; H.I., S.F., Y. Nonaka, M.F., S.M., S.O., K. Kano and J.A. performed in vitro and in vivo experiments; H.I. and S.M. designed aptamers; J.M. prepared the protein; R.I. and H.N. assisted with the structural analysis; and K. Kato, R.I., H.N., Y. Nakamura and O.N. wrote the manuscript with help from all authors. Y. Nakamura and O.N. directed and supervised all of the research.

Competing interests

Except for K. Kato, J.A., J.M., R.I., H.N. and O.N., all authors are either employees of Ribomic Inc. and/or hold equity in Ribomic Inc. The remaining authors declare no competing financial interests.

Corresponding authors

Correspondence to Yosuke Nonaka or Osamu Nureki.

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