{"title":"ATP水解诱导p -糖蛋白核苷酸结合域的构象变化。","authors":"Sepehr Dehghani-Ghahnaviyeh, Karan Kapoor, Emad Tajkhorshid","doi":"10.1002/1873-3468.13992","DOIUrl":null,"url":null,"abstract":"<p><p>P-glycoprotein (Pgp) is a member of the ABC transporter superfamily with high physiological importance. Pgp nucleotide-binding domains (NBDs) drive the transport cycle through ATP binding and hydrolysis. We use molecular dynamics simulations to investigate the ATP hydrolysis-induced conformational changes in NBDs. Five systems, including all possible ATP/ADP combinations in the NBDs and the APO system, are simulated. ATP/ADP exchange induces conformational changes mostly within the conserved signature motif of the NBDs, resulting in relative orientational changes in the NBDs. Nucleotide removal leads to additional orientational changes in the NBDs, allowing their dissociation. Furthermore, we capture putative hydrolysis-competent configurations in which the conserved glutamate in the Walker-B motif acts as a catalytic base capturing a water molecule likely initiating ATP hydrolysis.</p>","PeriodicalId":50454,"journal":{"name":"FEBS Letters","volume":"595 6","pages":"735-749"},"PeriodicalIF":3.0000,"publicationDate":"2021-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/1873-3468.13992","citationCount":"11","resultStr":"{\"title\":\"Conformational changes in the nucleotide-binding domains of P-glycoprotein induced by ATP hydrolysis.\",\"authors\":\"Sepehr Dehghani-Ghahnaviyeh, Karan Kapoor, Emad Tajkhorshid\",\"doi\":\"10.1002/1873-3468.13992\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>P-glycoprotein (Pgp) is a member of the ABC transporter superfamily with high physiological importance. Pgp nucleotide-binding domains (NBDs) drive the transport cycle through ATP binding and hydrolysis. We use molecular dynamics simulations to investigate the ATP hydrolysis-induced conformational changes in NBDs. Five systems, including all possible ATP/ADP combinations in the NBDs and the APO system, are simulated. ATP/ADP exchange induces conformational changes mostly within the conserved signature motif of the NBDs, resulting in relative orientational changes in the NBDs. Nucleotide removal leads to additional orientational changes in the NBDs, allowing their dissociation. Furthermore, we capture putative hydrolysis-competent configurations in which the conserved glutamate in the Walker-B motif acts as a catalytic base capturing a water molecule likely initiating ATP hydrolysis.</p>\",\"PeriodicalId\":50454,\"journal\":{\"name\":\"FEBS Letters\",\"volume\":\"595 6\",\"pages\":\"735-749\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2021-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1002/1873-3468.13992\",\"citationCount\":\"11\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"FEBS Letters\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1002/1873-3468.13992\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2020/12/10 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"FEBS Letters","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1002/1873-3468.13992","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2020/12/10 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 11
摘要
p -糖蛋白(Pgp)是ABC转运蛋白超家族的一员,具有很高的生理重要性。Pgp核苷酸结合域(nbd)通过ATP结合和水解驱动转运循环。我们利用分子动力学模拟研究ATP水解诱导的nbd构象变化。模拟了五种系统,包括nbd和APO系统中所有可能的ATP/ADP组合。ATP/ADP交换主要在nbd的保守特征基序内引起构象变化,导致nbd的相对取向变化。核苷酸的去除导致nbd的额外取向变化,允许它们解离。此外,我们捕获了假定的水解能力构型,其中Walker-B基序中的保守谷氨酸作为催化碱捕获可能启动ATP水解的水分子。
Conformational changes in the nucleotide-binding domains of P-glycoprotein induced by ATP hydrolysis.
P-glycoprotein (Pgp) is a member of the ABC transporter superfamily with high physiological importance. Pgp nucleotide-binding domains (NBDs) drive the transport cycle through ATP binding and hydrolysis. We use molecular dynamics simulations to investigate the ATP hydrolysis-induced conformational changes in NBDs. Five systems, including all possible ATP/ADP combinations in the NBDs and the APO system, are simulated. ATP/ADP exchange induces conformational changes mostly within the conserved signature motif of the NBDs, resulting in relative orientational changes in the NBDs. Nucleotide removal leads to additional orientational changes in the NBDs, allowing their dissociation. Furthermore, we capture putative hydrolysis-competent configurations in which the conserved glutamate in the Walker-B motif acts as a catalytic base capturing a water molecule likely initiating ATP hydrolysis.
期刊介绍:
FEBS Letters is one of the world''s leading journals in molecular biology and is renowned both for its quality of content and speed of production. Bringing together the most important developments in the molecular biosciences, FEBS Letters provides an international forum for Minireviews, Research Letters and Hypotheses that merit urgent publication.