Investigation of the drug-CYP3A4 interaction by the use of high resolution structure analysis

• Project/Area Number: 20790046
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Physical pharmacy
• Research Institution: Japan Atomic Energy Agency
• Principal Investigator: ADACHI Motoyasu Japan Atomic Energy Agency, 量子ビーム応用研究部門, 研究職 (60293958)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2010: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2008: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: P450 / 大腸菌発現 / 結晶構造解析 / シトクロームP450 / 医薬品代謝 / CYP3A4 / 構造活性相関 / システイン

Research Abstract

CYP3A4 is a key enzyme responsible for drug metabolism. The study in structure-function relationship of the enzyme is important with respect to design for new drug. However, it is difficult to obtain enough amount of recombinant CYP3A4 as a soluble protein. Thus, the preparation of CYP3A4 remains an important problem.

Research Products

• [Journal Article] Towards investigation of the inhibitor-recognition mechanisms of drug-target proteins by neutron crystallography. (2010)
  • Author(s): Kuroki, R., Okazaki, N., Adachi, M., Ohhara, T., Kurihara, K., Tamada, T.
  • Journal Title: Acta Crystallogr D Biol Crystallogr. 66 Pages: 1126-1130
  • Peer Reviewed
• [Journal Article] 中性子と放射光の相補的な利用による創薬標的タンパク質の立体構造解析 (2010)
  • Author(s): 黒木良太、玉田太郎、栗原和男、大原高志、安達基泰
  • Journal Title: 薬学雑誌 130巻 Pages: 657-664
  • NAID: 130000259451
  • Peer Reviewed
• [Journal Article] 中性子を用いた創薬標的蛋白質の立体構造解析 (2010)
  • Author(s): 安達基泰、黒木良太
  • Journal Title: 蛋白質核酸酵素 55巻 Pages: 82-87
  • NAID: 40016985468
  • Peer Reviewed
• [Journal Article] 中性子回折による創薬標的蛋白質の構造解析 (2010)
  • Author(s): 玉田太郎、安達基泰
  • Journal Title: RADIOISOTOPES誌 59 Pages: 299-308
  • NAID: 10026244847
  • Peer Reviewed
• [Journal Article] Small-sized human immunodeficiency virus type-1 protease inhibitors containing allophenylnorstatine to explore the S2' pocket. (2009)
  • Author(s): Hidaka, K., Kimura, T., Abdel-Rahman, H.M., Nguyen, J.T., McDaniel, K.F., Kohlbrenner, W.E., Molla, A., Adachi, M., Tamada, T., Kuroki, R., Katsuki, N., Tanaka, Y., Matsumoto, H., Wang, J., Hayashi, Y., Kempf, D.J., Kiso, Y.
  • Journal Title: J Med Chem. 52(23) Pages: 7604-7617
  • Peer Reviewed
• [Journal Article] Combined high-resolution neutron and X-ray analysis of inhibited elastase confirms the active-site oxyanion hole but rules against a low-barrier hydrogen bond. (2009)
  • Author(s): Tamada, T., Kinoshita, T., Kurihara, K., Adachi, M., Ohhara, T., Imai, K., Kuroki, R., Tada, T.
  • Journal Title: J Am Chem Soc. 131 Pages: 11033-11040
• [Journal Article] Structure of HIV-1 protease in complex with potent inhibitor KNI-272 determined by high-resolution X-ray and neutron crystallography. (2009)
  • Author(s): Adachi, M., Ohhara, T., Kurihara, K., Tamada, T., Honjo, E., Okazaki, N., Arai, S., Shoyama, Y., Kimura, K., Matsumura, H., Sugiyama, S., Adachi, H., Takano, K., Mori, Y., Hidaka, K., Kimura, T., Hayashi, Y., Kiso, Y., Kuroki, R.
  • Journal Title: Proc Natl Acad Sci USA. 106 Pages: 4641-4646
  • Peer Reviewed
• [Journal Article] HIV-1プロテアーゼの中性子結晶構造解析 (2009)
  • Author(s): 安達基泰, 黒木良太
  • Journal Title: 中性子科学会誌「波紋」 19 Pages: 214-217
  • NAID: 130006701970
  • Peer Reviewed
• [Journal Article] Crystallization and preliminary neutron diffraction studies of HIV-1 protease cocrystallized with inhibitor KNI-272. (2008)
  • Author(s): Matsumura, H., Adachi, M., Sugiyama, S., Okada, S., Yamakami, M., Tamada, T., Hidaka, K., Hayashi, Y., Kimura, T., Kiso, Y., Kitatani, T., Maki, S., Yoshikawa, H.Y., Adachi, H., Takano, K., Murakami, S., Inoue, T., Kuroki, R., Mori, Y.
  • Journal Title: Acta Crystallogr Sect F64 Pages: 1003-1006
  • Peer Reviewed
• [Journal Article] Mutagenesis of the crystal contact of acidic fibroblast growth factor. (2008)
  • Author(s): Honjo, E., Tamada, T., Adachi, M., Kuroki, R., Meher, A., Blaber, M.
  • Journal Title: J.Synchrotron Radiat. 15 Pages: 285-287
  • Peer Reviewed
• [Presentation] Structure of HIV-1 Protease in Complex with Potent Inhibitor KNI-272 Determined by Neutron Crystallography (2010)
  • Author(s): 安達基泰(代表者)
  • Organizer: The 5th International Peptide Symposium
  • Place of Presentation: 京都国際会議場(京都市)
  • Year and Date: 2010-12-09
• [Presentation] 放射光と中性子を相補的に用いたヒト免疫不全ウイルスプロテアーゼ阻害剤の立体構造解析 (2010)
  • Author(s): 安達基泰(代表者)
  • Organizer: 酵素工学研究会第64回講演会
  • Place of Presentation: 東京大学「山上会館」(東京都文京区)
  • Year and Date: 2010-11-19
• [Presentation] Structure of HIV-1 Protease in Complex with Inhibitor KNI-272 Determined by Neutron Crystallography (2010)
  • Author(s): 安達基泰(代表者)
  • Organizer: 11th China-Japan-Korean Joint Symposium on Enzyme Engineering[第11回日中韓酵素工学会議]
  • Place of Presentation: Green Land Hotel(中国成都)
  • Year and Date: 2010-11-07
• [Presentation] 薬剤耐性A17型HIV-1プロテアーゼと阻害剤複合体のX線結晶構造解析 (2010)
  • Author(s): 安達基泰(代表者)
  • Organizer: 第10回日本蛋白質科学会年会
  • Place of Presentation: 札幌コンベンションセンター(札幌市)
  • Year and Date: 2010-06-16
• [Presentation] Structure of HIV-1 Protease in Complex with Inhibitor KNI-272 Determined by Neutron Crystallography (2009)
  • Author(s): 安達基泰(代表者)
  • Organizer: Joint Conference of the Asian Crystallographic Association & Chinese Crystallography Society
  • Place of Presentation: Jingyi Hotel(中国北京)
  • Year and Date: 2009-10-24
• [Presentation] HIV-1プロテアーゼの中性子結晶構造解析 (2009)
  • Author(s): 安達基泰(代表者)
  • Organizer: 第9回日本蛋白質科学会年会
  • Place of Presentation: 熊本全日空ホテルニュースカイ(熊本市)
  • Year and Date: 2009-05-22
• [Presentation] Neutron Crystallography for Investigation of Catalytic Mechanism of HIV-1 Protease (2009)
  • Author(s): 安達基泰(代表者)
  • Organizer: ATI International Forum 2009 "Protein Structure Determination and Applications"
  • Place of Presentation: 原子力機構・テクノ交流館リコッティー(茨城県東海村)
  • Year and Date: 2009-03-10
• [Presentation] HIV-1プロテアーゼとKNI-272との複合体の中性子構造解析 (2008)
  • Author(s): 安達基泰(代表者)
  • Organizer: International Symposium on Integrated Medicinal Science-On the basis of traditional medicine to biomolecular system-
  • Place of Presentation: 京都薬科大学愛学館(京都市)
  • Year and Date: 2008-12-13
• [Presentation] HIV-1プロテアーゼの中性子結晶構造解析 (2008)
  • Author(s): 安達基泰
  • Organizer: 日本中性子科学会第8回年会
  • Place of Presentation: 名古屋大学東山キャンパス豊田講堂(名古屋市)
  • Year and Date: 2008-12-02
• [Book] 酵素利用技術体系(第2章酵素を見る。「医療関連酵素」)(小宮山眞監修) (2010)
  • Author(s): 安達基泰、角南智子、黒木良太
  • Publisher: エヌ・ティー・エス