Synthesis and biological evaluation on hMC3, hMC4 and hMC5 receptors of γ-MSH analogs substituted with L-alanine
Synthesis and biological evaluation on hMC3, hMC4 and hMC5 receptors of γ-MSH analogs substituted with L-alanine
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DOI：
10.1034/j.1399-3011.2002.01966.x
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发表时间：
2002-05-01
期刊：
影响因子：
--
通讯作者：
Hruby, VJ
中科院分区：
文献类型：
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作者：
Grieco, P;Balse-Srinivasan, P;Hruby, VJ
为了阐明天然十二肽γ-MSH与黑皮质素受体相互作用的分子基础，我们进行了结构-活性研究，在该研究中，我们系统地替换了该肽的每个位置中的L-Ala。在这里，我们报告了对人MC 3R、MC 4 R和MC 5 F的结合亲和力和激动剂效力。在CHO细胞上测量细胞内cAMP浓度，并使用由稳定表达hMC 3R、hMC 4 R和hMC 5 R的这些细胞系制备的膜进行结合测定。我们的研究结果表明，在γ-MSH的C-末端区域的最后四个氨基酸是不重要的生物活性和选择性在人类黑皮质素受体的决定因素。当用L-Ala取代His（6）、Phe（7）、Arg（8）和Trp（9）时，得到了有趣的结果。对于这些肽，对所有三种人受体（MC 3R、MC 4 R和MC 5 R）的亲和力和活性显著降低，证明γ-MSH中的His-Phe-Arg-Trp序列对于对这三种黑皮质素受体的活性是重要的。当Met（3）被L-Ala替换时获得了类似的结果，表明该位置在与所有三种受体的相互作用中的重要性。这项研究强调了His-Phe-Arg-Trp序列在Dates中所起的作用：受体结合和γ-MSH的激动剂活性。
To elucidate the molecular basis of the interaction of the native dodecapeptide gamma-MSH with the melanocortin receptors, we performed a structure-activity study in which we systematically replaced L-Ala in each position of this peptide. Here we report the binding affinity and agonist potency on human MC3R, MC4R and MC5F. Intracellular cAMP concentration was measured on CHO cells, and binding assays were carried out using membranes prepared from these cell lines which stably express hMC3R, hMC4R and hMC5R. Our results indicate that the last four amino acids in the C-terminal region of gamma-MSH are not important determinants of biological activity and selectivity at human melanocortin receptors. interesting results were obtained when L-Ala was substituted for His(6), Phe(7), Arg(8) and Trp(9). For these peptides, the affinity and activity at all three human receptors (MC3R, MC4R and MC5R) decreased significantly, demonstrating that the His-Phe-Arg-Trp sequence in gamma-MSH is important for activity at these three melanocortin receptors, Similar results were obtained when Met(3) was replaced with L-Ala, suggesting the importance of this position in the interaction with all three receptors. This study highlights the role played by the His-Phe-Arg-Trp sequence in Dates: receptor binding and in agonist activity of gamma-MSH.