Details

Autor(en) / Beteiligte

• Kato, Kazuki
• Ikeda, Hisako
• Miyakawa, Shin
• Futakawa, Satoshi
• Nonaka, Yosuke
• Fujiwara, Masatoshi
• Okudaira, Shinichi
• Kano, Kuniyuki
• Aoki, Junken
• Morita, Junko
• Ishitani, Ryuichiro
• Nishimasu, Hiroshi
• Nakamura, Yoshikazu
• Nureki, Osamu

Titel

Structural basis for specific inhibition of Autotaxin by a DNA aptamer

Ist Teil von

• Nature structural & molecular biology, 2016-05, Vol.23 (5), p.395-401

Ort / Verlag

United States

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.