Structural basis for specific inhibition of Autotaxin by a DNA aptamer

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aptamers, Nucleotide / chemistry*
  • Base Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • HEK293 Cells
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Inverted Repeat Sequences
  • Male
  • Mice, Inbred C57BL
  • Models, Molecular
  • Phosphodiesterase Inhibitors / chemistry
  • Phosphoric Diester Hydrolases / chemistry*
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Domains


  • Aptamers, Nucleotide
  • Phosphodiesterase Inhibitors
  • Phosphoric Diester Hydrolases
  • alkylglycerophosphoethanolamine phosphodiesterase