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Exploring receptor selectivity of the chimeric relaxin family peptide R3/I5 by incorporating unnatural amino acids
Biochimie ( IF 3.9 ) Pub Date : 2018-08-10 , DOI: 10.1016/j.biochi.2018.08.003
Jia-Hui Wang , Meng-Jun Hu , Lei Zhang , Xiao-Xia Shao , Cai-Hong Lv , Ya-Li Liu , Zeng-Guang Xu , Zhan-Yun Guo

Relaxin family peptides perform a variety of biological functions by activating four G protein-coupled receptors, namely RXFP1−4. Our recent study demonstrated that selectivity of the chimeric relaxin family peptide R3/I5 towards the homologous RXFP3 and RXFP4 can be modulated by replacement of the highly conserved nonchiral B23Gly or B24Gly with some natural l-amino acids. To investigate the mechanism of this modulating effect, in the present study we incorporated unnatural amino acids into the B23 or B24 position of a semi-synthetic R3/I5 that was prepared by a novel sortase-catalysed ligation approach using synthetic relaxin-3 B-chain and recombinant INSL5 A-chain. R3/I5 was a weak agonist for RXFP3 after B23Gly was replaced by D-Ala or D-Ser, but a strong antagonist for this receptor after B23Gly was replaced by corresponding l-amino acids. However, these replacements always resulted in a weak agonist for RXFP4. Thus, configuration of the B23 residue of R3/I5 affected activation of RXFP3 but not RXFP4. For the B24 residue, both size and configuration affected receptor selectivity of R3/I5. l-amino acids with an appropriate size, such as L-Ser and L-Abu, had the greatest effect on increasing the selectivity of R3/I5 towards RXFP3 over the homologous RXFP4. Our present results provided new insights into receptor selectivity of R3/I5, and would facilitate design of novel agonists or antagonists for RXFP3 and RXFP4 in future studies.



中文翻译:

通过掺入非天然氨基酸探索嵌合松弛素家族肽R3 / I5的受体选择性

松弛素家族肽通过激活四个G蛋白偶联受体RXFP1-4来执行多种生物学功能。我们最近的研究表明,嵌合松弛素家族肽R3 / I5对同源RXFP3和RXFP4的选择性可以通过用一些天然L取代高度保守的非手性B23Gly或B24Gly来调节-氨基酸。为了研究这种调节作用的机制,在本研究中,我们将非天然氨基酸掺入了半合成R3 / I5的B23或B24位置,该位置是通过使用合成松弛素3 B-的新型分选酶催化的连接方法制备的链和重组INSL5 A链。在B23Gly被D-Ala或D-Ser替代后,R3 / I5是RXFP3的弱激动剂,但是在B23Gly被相应的1-氨基酸替代后,R3 / I5对该受体的强拮抗剂。但是,这些替换总是导致RXFP4的激动剂弱。因此,R3 / I5的B23残基的配置影响RXFP3的激活,但不影响RXFP4的激活。对于B24残基,大小和构型均会影响R3 / I5的受体选择性。具有适当大小的α-氨基酸,例如L-Ser和L-Abu,与同源RXFP4相比,对提高R3 / I5对RXFP3的选择性具有最大的影响。我们目前的结果为R3 / I5的受体选择性提供了新的见解,并在将来的研究中将有助于设计RXFP3和RXFP4的新型激动剂或拮抗剂。

更新日期:2018-08-10
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