Structural basis for the interaction of isoDGR with the RGD-binding site of αvβ3 integrin
Structural basis for the interaction of isoDGR with the RGD-binding site of αvβ3 integrin
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DOI：
10.1074/jbc.m710273200
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发表时间：
2008-07-11
影响因子：
4.8
通讯作者：
Musco, Giovanna
中科院分区：
文献类型：
--
作者：
Spitaleri, Andrea;Mari, Silvia;Musco, Giovanna
在纤连蛋白（FN-1 -5）的第5个I型重复序列中的NGR序列处的天冬酰胺脱酰胺产生isoDGR，isoDGR是调节内皮细胞粘附和增殖的α v β 3整联蛋白结合基序。通过NMR和分子动力学研究，我们分析了模拟FN-I-5位点的环状β肽CisoDGRC（isoDGR-2C）的结构，并将其与NGR、RGD或含有DGR的环肽进行了比较。对接实验表明，isoDGR利用与RGD相比的反向取向，有利地与α v β 3的RGD结合位点相互作用，既重现了经典的RGD-α v β 3接触，又建立了额外的极性相互作用。相反，NGR和DGR基序缺乏高受体亲和力的基本药效学要求。因此，与NGR和DGR不同，isoDGR是α v β 3的RGD结合口袋的新的天然识别基序。这些发现有助于解释FN-I-5在脱酰胺前后的不同功能特性，并为NGR 3 isoDGR转换可作为分子计时器激活蛋白质中潜在的整合素结合位点从而调节蛋白质功能的假说提供支持。
Asparagine deamidation at the NGR sequence in the 5th type I repeat of fibronectin (FN-I-5) generates isoDGR, an alpha v beta 3 integrin-binding motif regulating endothelial cell adhesion and proliferation. By NMR and molecular dynamics studies, we analyzed the structure of CisoDGRC (isoDGR-2C), a cyclic beta-peptide mimicking the FN-I-5 site, and compared it with NGR, RGD, or DGR-containing cyclopeptides. Docking experiments show that isoDGR, exploiting an inverted orientation as compared with RGD, favorably interacts with the RGD-binding site of alpha v beta 3, both recapitulating canonical RGD-alpha v beta 3 contacts and establishing additional polar interactions. Conversely, NGR and DGR motifs lack the fundamental pharmacophoric requirements for high receptor affinity. Therefore, unlike NGR and DGR, isoDGR is a new natural recognition motif of the RGD-binding pocket of alpha v beta 3. These findings contribute to explain the different functional properties of FN-I-5 before and after deamidation, and provide support for the hypothesis that NGR 3 isoDGR transition can work as a molecular timer for activating latent integrin-binding sites in proteins, thus regulating protein function.