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DOI | 10.1126/science.aav9406 |
Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors | |
Dastvan, Reza1; Mishra, Smriti1; Peskova, Yelena B.2; Nakamoto, Robert K.2; Mchaourab, Hassane S.1 | |
2019-05-17 | |
发表期刊 | SCIENCE |
ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2019 |
卷号 | 364期号:6441页码:689-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | The ATP-binding cassette subfamily B member 1 (ABCB1) multidrug transporter P-glycoprotein plays a central role in clearance of xenobiotics in humans and is implicated in cancer resistance to chemotherapy. We used double electron electron resonance spectroscopy to uncover the basis of stimulation of P-glycoprotein adenosine 5'-triphosphate (ATP) hydrolysis by multiple substrates and illuminate how substrates and inhibitors differentially affect its transport function. Our results reveal that substrate-induced acceleration of ATP hydrolysis correlates with stabilization of a high-energy, post-ATP hydrolysis state characterized by structurally asymmetric nucleotide-binding sites. By contrast, this state is destabilized in the substrate-free cycle and by high-affinity inhibitors in favor of structurally symmetric nucleotide binding sites. Together with previous data, our findings lead to a general model of substrate and inhibitor coupling to P-glycoprotein. |
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:000468551000036 |
WOS关键词 | ELECTRON-ELECTRON RESONANCE ; DISTANCE MEASUREMENTS ; ATP HYDROLYSIS ; ABC TRANSPORTERS ; BINDING ; BIOMACROMOLECULES ; TRANSITION ; EFFLUX ; RANGE ; STATE |
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/201445 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA; 2.Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA |
推荐引用方式 GB/T 7714 | Dastvan, Reza,Mishra, Smriti,Peskova, Yelena B.,et al. Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors[J]. SCIENCE,2019,364(6441):689-+. |
APA | Dastvan, Reza,Mishra, Smriti,Peskova, Yelena B.,Nakamoto, Robert K.,&Mchaourab, Hassane S..(2019).Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors.SCIENCE,364(6441),689-+. |
MLA | Dastvan, Reza,et al."Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors".SCIENCE 364.6441(2019):689-+. |
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