title: Structural basis for specific inhibition of Autotaxin by a DNA aptamer.
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.
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kato
authors.affiliation: Ribomic Inc., Tokyo, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Ikeda
authors.affiliation: Ribomic Inc., Tokyo, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Miyakawa
authors.affiliation: Ribomic Inc., Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Futakawa
authors.affiliation: Ribomic Inc., Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nonaka
authors.affiliation: Ribomic Inc., Tokyo, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okudaira
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Kano
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Morita
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Ishitani
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishimasu
authors.affiliation: Ribomic Inc., Tokyo, Japan.|Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yoshikazu
authors.identifier: 0000-0001-8763-0424
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000737:chemistry*; D001483:Base Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D055029:Inverted Repeat Sequences; D008297:Male; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072417:Protein Domains; D000099189:Lysophospholipase D
chemical_list: D052157:Aptamers, Nucleotide; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D