Elucidation of Multidrug recognition mechanism of ABC transporter and development of its novel inhibitor

2015 Fiscal Year Final Research Report

• Project/Area Number: 25251006
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Kyoto University
• Principal Investigator: Kato Hiroaki 京都大学, 薬学研究科(研究院), 教授 (90204487)
• 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)
• Co-Investigator(Renkei-kenkyūsha): YAMAGUCHI Tomohiro 京都大学, 大学院薬学研究科, 助教 (80346791)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 生体膜 / 構造機能相関 / 受容体 / X線結晶構造解析

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.

Free Research Field

構造生物学