Development of nucleic acids therapeutics against multiple domains of transcription factor SATB1

• Project/Area Number: 24570144
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: National Institute of Advanced Industrial Science and Technology
• Principal Investigator: YAMASAKI Kazuhiko 独立行政法人産業技術総合研究所, バイオメディカル研究部門, 主任研究員 (00358243)
• Co-Investigator(Renkei-kenkyūsha): MIYAGISHI Makoto 独立行政法人産業技術総合研究所, バイオメディカル研究部門, 研究グループ長 (30323538) ; OKADA Tomoko 独立行政法人産業技術総合研究所, バイオメディカル研究部門, 上級主任研究員 (30344146)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 転写因子 / 核酸創薬 / がん / タンパク質核酸相互作用

Outline of Final Research Achievements

The scope of this project is to obtain nucleic acids that have inhibitory activities against transcription factor SATB1 through binding to its functional domains. We investigated properties of three DNA-binding domains by isothermal titration calorimetry and found that only one of them (CUTr1) is responsible for the sequence-specific DNA binding. By introducing phosphorothioate modification, we obtained a high-affinity nucleic acid especially under salt concentration close to biological condition. Crystal structure of complex of this nucleic acid and CUTr1 revealed that hydrophobic interactions between phosphorothioate and amino acid side chain are responsible for the high affinity.

Research Products

• [Journal Article] The combination of sequence-specific and nonspecific binding modes of transcription factor SATB1 (2016)
  • Author(s): Kazuhiko Yamasaki and Tomoko Yamasaki
  • Journal Title: Biochemical Journal Volume: 473 Issue: 19 Pages: 3321-3339
  • DOI: 10.1042/bcj20160236
  • Peer Reviewed
• [Presentation] 転写因子SATB1のDNA認識における弱い配列特異的結合と強い非特異的結合の組み合わせ (2014)
  • Author(s): 山崎和彦、山崎智子
  • Organizer: 第８７回日本生化学会大会
  • Place of Presentation: 京都国際会議場
  • Year and Date: 2014-10-16 – 2014-10-17
• [Presentation] 等温滴定型カロリメトリーとNMR分光によるタンパク質・核酸相互作用解 (2014)
  • Author(s): 山崎和彦、山崎智子
  • Organizer: GE Life Sciences Day 2014
  • Place of Presentation: パシフィコ横浜会議センター
  • Year and Date: 2014-08-01