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Nat Struct Mol Biol. 2016 May;23(5):395-401. doi: 10.1038/nsmb.3200. Epub 2016 Apr 4.

Structural basis for specific inhibition of Autotaxin by a DNA aptamer.

Author information

1
Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan.
2
Ribomic Inc., Tokyo, Japan.
3
Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
4
Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Tokyo, Japan.
5
Institute of Medical Science, University of Tokyo, Tokyo, Japan.

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.

PMID:
27043297
DOI:
10.1038/nsmb.3200
[Indexed for MEDLINE]

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