Elucidation of the molecular mechanism of ABC transporters

• Project/Area Number: 24689029
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Partial Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Kyoto University
• Principal Investigator: KODAN Atsushi 京都大学, 物質ー細胞統合システム拠点, 助教 (80360543)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥22,100,000 (Direct Cost: ¥17,000,000、Indirect Cost: ¥5,100,000); Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2013: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2012: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000)
• Keywords: 生体分子 / 膜タンパク質 / 癌 / 多剤耐性 / 立体構造解析 / X線結晶構造解析 / ABCタンパク質 / P糖タンパク質 / 蛋白質 / 薬学

Outline of Final Research Achievements

In this study, the highest-resolution crystal structures of a eukaryotic P-glycoprotein homolog from the red algae Cyanidioschyzon merolae, were determined in two forms: unbound at 2.6-angstrom resolution and bound to a unique allosteric inhibitor at 2.4-angstrom resolution. These structures, along with site-directed mutagenesis and transporter activity measurements, reveal the detailed architecture of the transporter, including a gate that opens to extracellular side and two gates that open to intramembranous region and the cytosolic side.

Research Products

• [Journal Article] Structural basis for gating mechanisms of a eukaryotic P-glycoprotein homolog (2014)
  • Author(s): Atsushi Kodan, Tomohiro Yamaguchi, Toru Nakatsu, Keita Sakiyama, Christopher Hipolito, Akane Fujioka, Ryo Hirokane, Keiji Ikeguchi, Bunta Watanabe, Jun Hiratake, Yasuhisa Kimura, Hiroaki Suga, Kazumitsu Ueda, Hiroaki Kato
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 111 Issue: 11 Pages: 4049-4054
  • DOI: 10.1073/pnas.1321562111
  • Peer Reviewed
• [Presentation] ABC多剤排出トランスポーターの立体構造の特徴 (2014)
  • Author(s): 山口知宏、小段篤史、中津亨、植田和光、加藤博章
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] High-resolution crystal structure of an ABC multidrug exporter from Cyanidioschyzon merolae, a thermophilic unicellular eukaryote. (2014)
  • Author(s): Atsushi Kodan, Tomohiro Yamaguchi, Toru Nakatsu, Keita Sakiyama, Christopher J. Hipolito, Akane Fujioka, Ryo Hirokane, Yasuhisa Kimura, Hiroaki Suga, Kazumitsu Ueda, Hiroaki Kato
  • Organizer: ABC2014, the 5th FEBS Special Meeting “ ATP-Binding Cassette Proteins: From Multidrug Resistance to Genetic Disease”
  • Place of Presentation: Innsbruck, Austria
• [Presentation] Structure-based functional aspects of the ABC multidrug transporter, CmABCB1 from a thermophilic eukaryote. (2014)
  • Author(s): Tomohiro Yamaguchi, Atsushi Kodan, Toru Nakatsu, Keita Sakiyama, Christopher J. Hipolito, Akane Fujioka, Ryo Hirokane, Yasuhisa Kimura, Hiroaki Suga, Kazumitsu Ueda, Hiroaki Kato
  • Organizer: ABC2014, the 5th FEBS Special Meeting “ ATP-Binding Cassette Proteins: From Multidrug Resistance to Genetic Disease”
  • Place of Presentation: Innsbruck, Austria
• [Presentation] ABC多剤排出トランスポーターにおける基質取込の立体構造基盤 (2014)
  • Author(s): 山口 知宏、小段 篤史、中津 亨、植田 和光、加藤 博章
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本市
• [Presentation] 好熱性真核生物の ABC 多剤排出トランスポーターの X 線結晶構造解析 / Crystal structure of a eukaryotic ABC multi-drug transporter (2013)
  • Author(s): 廣兼 諒、小段 篤史、中津 亨、山口 知宏、植田 和光、加藤 博章
  • Organizer: 第13回日本蛋白質科学会年会
  • Place of Presentation: 鳥取市
• [Presentation] 好熱性紅藻由来ABCトランスポーターの輸送基質特異性の検討 (2012)
  • Author(s): 山口知宏、木村泰久、小段篤史、池口圭司、渡辺文太、平竹潤、中津亨、
  • Organizer: 第34回 生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 京都大学薬学部(京都府)
  • Year and Date: 2012-11-16
• [Presentation] 結晶構造に基づく多剤排出型ABCトランスポーターメカニズムの解明 (2012)
  • Author(s): 藤岡あかね、山口知宏、小段篤史、中津亨、植田和光、加藤博章
  • Organizer: 第日回 次世代を担う若手ファーマ・バイオフォーラム
  • Place of Presentation: 九州大学病院キャンパス コラボI(福岡県)
  • Year and Date: 2012-09-16
• [Remarks] 京都大学ホームページ
  • URL: http://www.kyoto-u.ac.jp/static/ja/news_data/h/h1/news6/2013_1/140220_1.htm