Structural basis for specific inhibition of Autotaxin by a DNA aptamer

• Published in: Nature structural & molecular biology Vol. 23; no. 5; pp. 395 - 401
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2016; Nature Publishing Group
• Subjects: 631/154; 631/535/1266; Animals; Aptamers, Nucleotide - chemistry; Base Sequence; Binding Sites; Biochemistry; Biological Microscopy; Chemokines; Crystal structure; Crystallography, X-Ray; Deoxyribonucleic acid; DNA; DNA-ligand interactions; HEK293 Cells; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Inverted Repeat Sequences; Life Sciences; Male; Membrane Biology; Mice, Inbred C57BL; Models, Molecular; Molecular biology; Nucleic acids; Oligonucleotides; Phosphodiesterase Inhibitors - chemistry; Phosphoric Diester Hydrolases - chemistry; Physiological aspects; Properties; Protein Binding; Protein Conformation, alpha-Helical; Protein Domains; Protein Structure; Ribonucleic acid; RNA; Japan
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.3200

SELEX selections and crystallographic analyses have allowed development of a DNA aptamer that inhibits autotaxin with high potency and specificity, and exhibits efficacy against bleomycin-induced pulmonary fibrosis in model mice.
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.