Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 23, Issue 5, Pages 395-401Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3200
Keywords
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Funding
- Core Research for Evolutional Science and Technology Program, the Creation of Basic Chronic Inflammation, from the Japan Science and Technology Agency
- NEDO
- Grants-in-Aid for Scientific Research [15J08403] Funding Source: KAKEN
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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-angstrom 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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