Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5

doi:10.1038/s41467-021-25574-8

	Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5
	Harris, Andrzej 1; Wagner, Manuel 2,8; Du, Dijun1,9 ; Raschka, Stefanie 2; Nentwig, Lea-Marie 2; Gohlke, Holger 3,4,5,6; Smits, Sander H. J.2,7; Luisi, Ben F.1; Schmitt, Lutz 2
	2021-09-06
发表期刊	NATURE COMMUNICATIONS (IF:14.7[JCR-2023],16.1[5-Year])
EISSN	2041-1723
卷号	12 期号:1
DOI	10.1038/s41467-021-25574-8
摘要	Pdr5, a member of the extensive ABC transporter superfamily, is representative of a clinically relevant subgroup involved in pleiotropic drug resistance. Pdr5 and its homologues drive drug efflux through uncoupled hydrolysis of nucleotides, enabling organisms such as baker's yeast and pathogenic fungi to survive in the presence of chemically diverse antifungal agents. Here, we present the molecular structure of Pdr5 solved with single particle cryo-EM, revealing details of an ATP-driven conformational cycle, which mechanically drives drug translocation through an amphipathic channel, and a clamping switch within a conserved linker loop that acts as a nucleotide sensor. One half of the transporter remains nearly invariant throughout the cycle, while its partner undergoes changes that are transmitted across inter-domain interfaces to support a peristaltic motion of the pumped molecule. The efflux model proposed here rationalises the pleiotropic impact of Pdr5 and opens new avenues for the development of effective antifungal compounds. Pdr5 is an ABC transporter conferring multidrug resistance to pathogenic fungi. Here, structural analysis of Pdr5 provides insights into the transport mechanism featuring asymmetric movements of Pdr5 domain and enabling efflux of a broad spectrum of compounds.
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收录类别	SCIE
语种	英语
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000694666900027
出版者	NATURE PORTFOLIO
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/128240
专题	生命科学与技术学院_PI研究组_杜迪军组
通讯作者	Luisi, Ben F.; Schmitt, Lutz
作者单位	1.Univ Cambridge, Dept Biochem, Cambridge, England; 2.Heinrich Heine Univ Dusseldorf, Inst Biochem, Univ Str 1, Dusseldorf, Germany; 3.Heinrich Heine Univ Dusseldorf, Inst Pharmaceut & Med Pharm, Univ Str 1, Dusseldorf, Germany; 4.Forschungszentrum Julich, Julich Supercomp Ctr JSC, John von Neumann Inst Comp NIC, Julich, Germany; 5.Forschungszentrum Julich, Inst Biol Informat Proc IBI Struct Biochem 7, Julich, Germany; 6.Forschungszentrum Julich, Inst Bio & Geosci IBG Bioinformat 4, Julich, Germany; 7.Heinrich Heine Univ Dusseldorf, Ctr Struct Studies, Univ Str 1, Dusseldorf, Germany; 8.Medac GmbH, Theatherstr 6, Wedel, Germany; 9.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Harris, Andrzej,Wagner, Manuel,Du, Dijun,et al. Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5[J]. NATURE COMMUNICATIONS,2021,12(1).
APA	Harris, Andrzej.,Wagner, Manuel.,Du, Dijun.,Raschka, Stefanie.,Nentwig, Lea-Marie.,...&Schmitt, Lutz.(2021).Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5.NATURE COMMUNICATIONS,12(1).
MLA	Harris, Andrzej,et al."Structure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5".NATURE COMMUNICATIONS 12.1(2021).