The relationship between substrate-interaction and conformational change in the transport of ABC transporters

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07320
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biophysics
• Research Institution: Kyoto University
• Principal Investigator: Yamaguchi Tomohiro 京都大学, 薬学研究科, 助教 (80346791)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ABCトランスポーター / P糖タンパク質 / 立体構造解析 / 変異体解析 / 膜タンパク質

Outline of Final Research Achievements

ABC transporters transport substrates in association with conformational change between the inward- and outward-facing states. We have determined these two state structures of an ABC multidrug transporter P-glycoprotein homolog, CmABCB1, at high resolution, and thus became to elucidate the relationship between conformational change and substrate transport. In this study, a crystal structure at an intermediate state of CmABCB1 mutant was determined. By comparison with the inward- and outward-structures of CmABCB1, this intermediate structure suggested that the interaction with a substrate was altered in conformational change. The mutation of the amino acid residues contributing the change the substrate interaction disrupted the transport activity. These results suggest that P-glycoprotein transports substrates by weakening the interaction of substrates by contracting the inner cavity involving substrate binding sites.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

本研究成果からは、P糖タンパク質が多様な基質を排出することができる理由が、基質結合部位がある空洞を収縮して基質との相互作用を弱めて細胞外に運ぶことによることが示唆された。特定の相互作用が寄与しないこの輸送メカニズムからは、ヒトABCB1の構造変化に作用することが排出されにくい薬剤の創製に対して新しい視点を与えると期待される。