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DOI | 10.1111/gcb.13386 |
Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein | |
Verhalen, Brandy1,5; Dastvan, Reza1; Thangapandian, Sundarapandian2,3; Peskova, Yelena4; Koteiche, Hanane A.1; Nakamoto, Robert K.4; Tajkhorshid, Emad2,3; Mchaourab, Hassane S.1 | |
2017-03-30 | |
发表期刊 | NATURE
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ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2017 |
卷号 | 543期号:7647页码:738-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | ATP binding cassette (ABC) transporters of the exporter class harness the energy of ATP hydrolysis in the nucleotide-binding domains (NBDs) to power the energetically uphill efflux of substrates by a dedicated transmembrane domain (TMD)(1-4). Although numerous investigations have described the mechanism of ATP hydrolysis and defined the architecture of ABC exporters, a detailed structural dynamic understanding of the transduction of ATP energy to the work of substrate translocation remains elusive. Here we used double electron-electron resonance(5,6) and molecular dynamics simulations to describe the ATP- and substrate-coupled conformational cycle of the mouse ABC efflux transporter P-glycoprotein (Pgp; also known as ABCB1), which has a central role in the clearance of xenobiotics and in cancer resistance to chemotherapy(7). Pairs of spin labels were introduced at residues selected to track the putative inward-facing to outward-facing transition. Our findings illuminate how ATP energy is harnessed in the NBDs in a two-stroke cycle and elucidate the consequent conformational motion that reconfigures the TMD, two critical aspects of Pgp transport mechanism. Along with a fully atomistic model of the outward-facing conformation in membranes, the insight into Pgp conformational dynamics harmonizes mechanistic and structural data into a novel perspective on ATP-coupled transport and reveals mechanistic divergence within the efflux class of ABC transporters. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000397619700060 |
WOS关键词 | NUCLEOTIDE-BINDING DOMAINS ; GUI MEMBRANE-BUILDER ; ATP HYDROLYSIS ; GLUTAMATE RESIDUES ; CATALYTIC CYCLE ; DISTANCE MEASUREMENTS ; MOLECULAR-DYNAMICS ; FORCE-FIELD ; CHARMM ; SIMULATIONS |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/16818 |
专题 | 气候变化 资源环境科学 |
作者单位 | 1.Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA; 2.Univ Illinois, Dept Biochem, Ctr Biophys & Quantitat Biol, Urbana, IL 61801 USA; 3.Univ Illinois, Beckman Inst Adv Sci & Technol, Urbana, IL 61801 USA; 4.Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA; 5.Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA |
推荐引用方式 GB/T 7714 | Verhalen, Brandy,Dastvan, Reza,Thangapandian, Sundarapandian,et al. Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein[J]. NATURE,2017,543(7647):738-+. |
APA | Verhalen, Brandy.,Dastvan, Reza.,Thangapandian, Sundarapandian.,Peskova, Yelena.,Koteiche, Hanane A..,...&Mchaourab, Hassane S..(2017).Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein.NATURE,543(7647),738-+. |
MLA | Verhalen, Brandy,et al."Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein".NATURE 543.7647(2017):738-+. |
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