| 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 |
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| Section | 一般 |
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| Research Field |
Structural biochemistry
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| Research Institution | Kyoto University |
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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 |
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| 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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