Elucidation of Multidrug recognition mechanism of ABC transporter and development of its novel inhibitor
Project/Area Number |
25251006
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Structural biochemistry
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Research Institution | Kyoto University |
Principal Investigator |
Kato Hiroaki 京都大学, 薬学研究科(研究院), 教授 (90204487)
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Co-Investigator(Kenkyū-buntansha) |
WATANABE Bunta 京都大学, 化学研究所, 助教 (10544637)
NAKATSU Toru 京都大学, 大学院薬学研究科, 准教授 (50293949)
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Co-Investigator(Renkei-kenkyūsha) |
YAMAGUCHI Tomohiro 京都大学, 大学院薬学研究科, 助教 (80346791)
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Project Period (FY) |
2013-04-01 – 2016-03-31
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Project Status |
Completed (Fiscal Year 2015)
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Budget Amount *help |
¥43,030,000 (Direct Cost: ¥33,100,000、Indirect Cost: ¥9,930,000)
Fiscal Year 2015: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000)
Fiscal Year 2014: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000)
Fiscal Year 2013: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000)
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Keywords | 生体膜 / 構造機能相関 / 受容体 / X線結晶構造解析 / 生体膜及び受容体 / ABCトランスポーター / 多剤耐性 / X線結晶解析 / 薬理学 |
Outline of Final Research Achievements |
We discovered an ATP binding cassette (ABC) multidrug transporter of which amino acid sequence and transporter function are very similar to those of human P-glycoprotein from a thermophilic eukaryote, Cyanidioschyzon merolae, and we named CmABCB1. The crystal structure of CmABCB1 complexed with its specific inhibitor, aCAP at 2.4 A resolution. This is the structure determination of an ABC transporter at the highest resolution in the year 2014. The inhibitor aCAP has a unique binding mechanism by which it clamps the transmembrane helices from the outside, fixing the CmABCB1 structure in an inward-open conformation. Using structure-based mutagenesis, we defined several important residues that act as a substrate gatekeeper, a transition switch, and a substrate hook associated with the underlying transport mechanism. These studies provide mechanistic insight into substrate recognition and transport by ABCB1 type of multidrug transporters, as well as a blueprint for drug development.
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Report
(4 results)
Research Products
(26 results)
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[Journal Article] Structural basis for gating mechanisms of a eukaryotic P-glycoprotein homolog2014
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
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Journal Title
Proceedings of the National Academy of Sciences of the United States of America
Volume: 111
Issue: 11
Pages: 4049-4054
DOI
Related Report
Peer Reviewed
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[Presentation] Serial Femtosecond Crystallography of ABC Transporter2016
Author(s)
Oyama Ryo, Pan Dongqing, Nakatsu Toru, Sato Tomomi, Yamaguchi Tomohiro, Kodan Atsushi, Ueda Kazumitsu, Iwata So, Kato Hiroaki
Organizer
6th Special Meeting, ATP-Binding Cassette (ABC) Proteins: From Multidrug Resistance to Genetic Diseases
Place of Presentation
Innsbruck (Austria)
Year and Date
2016-03-05
Related Report
Int'l Joint Research
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[Presentation] High-resolution crystal structure of an ABC multidrug exporter from Cyanidioschyzon merolae, a thermophilic unicellular eukaryote2014
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, 5th FEBS Special Meeting, ATP-Binding Cassette (ABC) Proteins: From Multidrug Resistance to Genetic Diseases
Place of Presentation
Hotel Grauer Bär (Innsbruck, Austria)
Related Report
Invited
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[Presentation] Structure-based functional aspects of the ABC multidrug transporter, CmABCB1 from a thermophilic eukaryote2014
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, 5th FEBS Special Meeting, ATP-Binding Cassette (ABC) Proteins: From Multidrug Resistance to Genetic Diseases
Place of Presentation
Hotel Grauer Bär (Innsbruck, Austria)
Related Report
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