Development of a selective agonist for relaxin family peptide receptor 3.
Development of a selective agonist for relaxin family peptide receptor 3.
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松弛素家族肽受体3选择性激动剂的开发
DOI：
10.1038/s41598-017-03465-7
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发表时间：
2017-06-12
影响因子：
4.6
通讯作者：
Guo ZY
中科院分区：
文献类型：
--
作者：
Wei D;Hu MJ;Shao XX;Wang JH;Nie WH;Liu YL;Xu ZG;Guo ZY
松弛素家族肽通过激活四种G蛋白偶联受体，即RXFP 1 -4，来执行多种生物学功能。在这些受体中，RXFP 3目前缺乏特异性天然或合成激动剂。先前设计的嵌合R3/I5肽，由松弛素-3的B链和INSL 5的A链组成，对同源RXFP 3和RXFP 4显示出相等的活性。为了增加其对RXFP 3的选择性，在本研究中，我们围绕R3/I5的B链C末端区域进行了广泛的诱变。减少或增加B23-B25位置周围的肽长度显著降低了R3/I5对RXFP 3和RXFP 4的活化效力。用Ala或Ser取代B23 Gly将R3/I5从有效的激动剂转化为RXFP 3的强拮抗剂，但突变体保留了对RXFP 4的相当大的激活效力。B24 Gly的取代增加了R3/I5相对于同源RXFP 4对RXFP 3的选择性。最佳突变体[G（B24）S]R3/I5对RXFP 3的激活效力比对RXFP 4的激活效力高20倍，同时保留了对RXFP 3的完全激活效力。因此，[G（B24）S]R3/I5是迄今为止已知的最好的RXFP 3选择性激动剂。这为研究RXFP 3的生理功能提供了有价值的工具，也为将来开发RXFP 3特异性激动剂提供了合适的模板。
Relaxin family peptides perform a variety of biological functions by activating four G protein-coupled receptors, namely RXFP1–4. Among these receptors, RXFP3 lacks a specific natural or synthetic agonist at present. A previously designed chimeric R3/I5 peptide, consisting of the B-chain of relaxin-3 and the A-chain of INSL5, displays equal activity towards the homologous RXFP3 and RXFP4. To increase its selectivity towards RXFP3, in the present study we conducted extensive mutagenesis around the B-chain C-terminal region of R3/I5. Decreasing or increasing the peptide length around the B23–B25 position dramatically lowered the activation potency of R3/I5 towards both RXFP3 and RXFP4. Substitution of B23Gly with Ala or Ser converted R3/I5 from an efficient agonist to a strong antagonist for RXFP3, but the mutants retained considerable activation potency towards RXFP4. Substitution of B24Gly increased the selectivity of R3/I5 towards RXFP3 over the homologous RXFP4. The best mutant, [G(B24)S]R3/I5, displayed 20-fold higher activation potency towards RXFP3 than towards RXFP4, meanwhile retained full activation potency at RXFP3. Thus, [G(B24)S]R3/I5 is the best RXFP3-selective agonist known to date. It is a valuable tool for investigating the physiological functions of RXFP3, and also a suitable template for developing RXFP3-specific agonists in future.