粘连蛋白肽调节血脑屏障的机制。

Exploration of drug science Pub Date : 2024-01-01 Epub Date: 2024-06-26 DOI:10.37349/eds.2024.00049
Elinaz Farokhi, Ahmed L Alaofi, Vivitri D Prasasty, Filia Stephanie, Marlyn D Laksitorini, Krzysztof Kuczera, Teruna J Siahaan
{"title":"粘连蛋白肽调节血脑屏障的机制。","authors":"Elinaz Farokhi, Ahmed L Alaofi, Vivitri D Prasasty, Filia Stephanie, Marlyn D Laksitorini, Krzysztof Kuczera, Teruna J Siahaan","doi":"10.37349/eds.2024.00049","DOIUrl":null,"url":null,"abstract":"<p><strong>Aim: </strong>This study was aimed at finding the binding site on the human E-cadherin for Ala-Asp-Thr Cyclic 5 (ADTC5), ADTC7, and ADTC9 peptides as blood-brain barrier modulator (BBBM) for determining their mechanism of action in modulating the blood-brain barrier (BBB).</p><p><strong>Methods: </strong>ADTC7 and ADTC9 were derivatives of ADTC5 where the Val6 residue in ADTC5 was replaced by Glu6 and Tyr6 residues, respectively. The binding properties of ADTC5, ADTC7, and ADTC9 to the extracellular-1 (EC1) domain of E-cadherin were evaluated using chemical shift perturbation (CSP) method in the two dimensional (2D) <sup>1</sup>H-<sup>15</sup>N-heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) spectroscopy. Molecular docking experiments were used to determine the binding sites of these peptides to the EC1 domain of E-cadherin.</p><p><strong>Results: </strong>This study indicates that ADTC5 has the highest binding affinity to the EC1 domain of E-cadherin compared to ADTC7 and ADTC9, suggesting the importance of the Val6 residue as shown in our previous in vitro study. All three peptides have a similar binding site at the hydrophobic binding pocket where the domain swapping occurs. ADTC5 has a higher overlapping binding site with ADTC7 than that of ADTC9. Binding of ADTC5 on the EC1 domain influences the conformation of the EC1 C-terminal tail.</p><p><strong>Conclusions: </strong>These peptides bind the domain swapping region of the EC1 domain to inhibit the <i>trans</i>-cadherin interaction that creates intercellular junction modulation to increase the BBB paracellular porosity.</p>","PeriodicalId":72998,"journal":{"name":"Exploration of drug science","volume":"2 3","pages":"322-338"},"PeriodicalIF":0.0000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309765/pdf/","citationCount":"0","resultStr":"{\"title\":\"Mechanism of the blood-brain barrier modulation by cadherin peptides.\",\"authors\":\"Elinaz Farokhi, Ahmed L Alaofi, Vivitri D Prasasty, Filia Stephanie, Marlyn D Laksitorini, Krzysztof Kuczera, Teruna J Siahaan\",\"doi\":\"10.37349/eds.2024.00049\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aim: </strong>This study was aimed at finding the binding site on the human E-cadherin for Ala-Asp-Thr Cyclic 5 (ADTC5), ADTC7, and ADTC9 peptides as blood-brain barrier modulator (BBBM) for determining their mechanism of action in modulating the blood-brain barrier (BBB).</p><p><strong>Methods: </strong>ADTC7 and ADTC9 were derivatives of ADTC5 where the Val6 residue in ADTC5 was replaced by Glu6 and Tyr6 residues, respectively. The binding properties of ADTC5, ADTC7, and ADTC9 to the extracellular-1 (EC1) domain of E-cadherin were evaluated using chemical shift perturbation (CSP) method in the two dimensional (2D) <sup>1</sup>H-<sup>15</sup>N-heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) spectroscopy. Molecular docking experiments were used to determine the binding sites of these peptides to the EC1 domain of E-cadherin.</p><p><strong>Results: </strong>This study indicates that ADTC5 has the highest binding affinity to the EC1 domain of E-cadherin compared to ADTC7 and ADTC9, suggesting the importance of the Val6 residue as shown in our previous in vitro study. All three peptides have a similar binding site at the hydrophobic binding pocket where the domain swapping occurs. ADTC5 has a higher overlapping binding site with ADTC7 than that of ADTC9. Binding of ADTC5 on the EC1 domain influences the conformation of the EC1 C-terminal tail.</p><p><strong>Conclusions: </strong>These peptides bind the domain swapping region of the EC1 domain to inhibit the <i>trans</i>-cadherin interaction that creates intercellular junction modulation to increase the BBB paracellular porosity.</p>\",\"PeriodicalId\":72998,\"journal\":{\"name\":\"Exploration of drug science\",\"volume\":\"2 3\",\"pages\":\"322-338\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309765/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Exploration of drug science\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.37349/eds.2024.00049\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/26 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Exploration of drug science","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.37349/eds.2024.00049","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/26 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

目的:本研究旨在寻找作为血脑屏障调节剂(BBBM)的Ala-Asp-Thr Cyclic 5(ADTC5)、ADTC7和ADTC9多肽在人E-cadherin上的结合位点,以确定其调节血脑屏障(BBB)的作用机制:ADTC7和ADTC9是ADTC5的衍生物,ADTC5中的Val6残基分别被Glu6和Tyr6残基取代。在二维(2D)1H-15N-异核单量子相干(HSQC)核磁共振(NMR)光谱中使用化学位移扰动(CSP)方法评估了ADTC5、ADTC7和ADTC9与E-cadherin的胞外-1(EC1)结构域的结合特性。分子对接实验用于确定这些肽与 E-cadherin EC1 结构域的结合位点:这项研究表明,与 ADTC7 和 ADTC9 相比,ADTC5 与 E-cadherin EC1 结构域的结合亲和力最高,这表明 Val6 残基的重要性正如我们之前的体外研究所示。这三种肽在发生结构域交换的疏水结合袋上都有相似的结合位点。与 ADTC9 相比,ADTC5 与 ADTC7 的结合位点重叠度更高。ADTC5 与 EC1 结构域的结合会影响 EC1 C 端尾部的构象:这些肽结合了 EC1 结构域的结构域交换区,从而抑制了跨粘连蛋白的相互作用,这种相互作用产生了细胞间连接调节,从而增加了 BBB 的细胞旁孔隙率。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mechanism of the blood-brain barrier modulation by cadherin peptides.

Aim: This study was aimed at finding the binding site on the human E-cadherin for Ala-Asp-Thr Cyclic 5 (ADTC5), ADTC7, and ADTC9 peptides as blood-brain barrier modulator (BBBM) for determining their mechanism of action in modulating the blood-brain barrier (BBB).

Methods: ADTC7 and ADTC9 were derivatives of ADTC5 where the Val6 residue in ADTC5 was replaced by Glu6 and Tyr6 residues, respectively. The binding properties of ADTC5, ADTC7, and ADTC9 to the extracellular-1 (EC1) domain of E-cadherin were evaluated using chemical shift perturbation (CSP) method in the two dimensional (2D) 1H-15N-heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) spectroscopy. Molecular docking experiments were used to determine the binding sites of these peptides to the EC1 domain of E-cadherin.

Results: This study indicates that ADTC5 has the highest binding affinity to the EC1 domain of E-cadherin compared to ADTC7 and ADTC9, suggesting the importance of the Val6 residue as shown in our previous in vitro study. All three peptides have a similar binding site at the hydrophobic binding pocket where the domain swapping occurs. ADTC5 has a higher overlapping binding site with ADTC7 than that of ADTC9. Binding of ADTC5 on the EC1 domain influences the conformation of the EC1 C-terminal tail.

Conclusions: These peptides bind the domain swapping region of the EC1 domain to inhibit the trans-cadherin interaction that creates intercellular junction modulation to increase the BBB paracellular porosity.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信