Novel binding motif of ACTH analogues at the melanocortin receptors.
Novel binding motif of ACTH analogues at the melanocortin receptors.
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黑色素皮质素受体的ACTH类似物的新型结合基序。
DOI：
10.1021/bi900634e
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发表时间：
2009-10-20
期刊：
影响因子：
2.9
通讯作者：
Harmon, Carroll M.
中科院分区：
文献类型：
--
作者：
Yang, Yingkui;Hruby, Victor J.;Chen, Min;Crasto, Chiquito;Cai, Minying;Harmon, Carroll M.
黑素皮质素受体(MCR)亚型家族是GPCR超家族的成员之一，对于内源性和合成黑素皮质素多肽的相对效力，每个亚型家族都有不同的药理学特征。α-MSH和ACTH是MC1R、MC3R、MC4R和MC5R的内源性非选择性激动剂。在这项研究中，我们研究了Phe7在ACTH中对人(H)MC1R、MC3R和MC4R结合和信号转导的作用。我们的结果表明，在hMC1R、hMC3R和hMC4R中，在ACTH1-24中用DNAL(2‘)7替换Phe7与在MSH中用DNAL(2’)7替换Phe7具有不同的药理特性。NDNAL(2‘)7-ACTH1-24是hMC3R和hMC4R上的激动剂，在hMC3R和hMC4R上不能从激动剂转换为拮抗剂。进一步的实验表明，NDNal(2‘)7-ACTH1-17是hMC3R和hMC4R激活所需的最小肽。DNAL(2‘)7 ACTH1-17的单一氨基酸替代研究表明，NDNAL(2’)7-ACTH1-17的15、16和17位氨基酸残基对hMC3R和hMC4R的激活起关键作用。这些氨基酸残基的取代降低或取消了hMC3R和hMC4R的激动剂活性。构象研究发现，在NDNAL(2‘)7-ACTH1-17中有一个新的β-Turn(-Arg8-Trp9-Gly10-Lys11-)，而在Ndp-β-MSh(-His6-DPhe7-Arg8-Trp9-)中有一个类似α-Turn的结构。我们的结果表明，NDNAL(2‘)7-α-17与NDNAL(2’)7-ACTH1-17不具有相同的结合部位，NDNAL(2‘)7-ACTH1-17的高碱性C末端片段Lys15-Lys16-Arg17诱导了一个新的β-Turn，这一转变有助于在hMC3R和hMC4R处产生选择性激动剂活性。
The melanocortin receptor (MCR) subtype family is a member of the GPCR superfamily and each of them has a different pharmacological profile regarding the relative potency of the endogenous and synthetic melanocortin peptides. α-MSH and ACTH are endogenous nonselective agonists for MC1R, MC3R, MC4R and MC5R. In this study, we examined the role of Phe7 in ACTH on Human (h)MC1R, MC3R and MC4R binding and signaling. Our results indicate that substitution of the Phe7 with DNal (2’)7 in ACTH1-24 has different pharmacological profile from that of substitution of the Phe7 with DNal (2’)7 in MSH at hMC1R, hMC3R and hMC4R. NDNal (2’)7-ACTH1-24 is an agonist at hMC3R and hMC4R which did not switch peptide from agonist to antagonist at hMC3R and hMC4R. Further experiments indicate that NDNal (2’)7-ACTH1-17 is the minimal peptide required for hMC3R and hMC4R activation. Single amino acid substitution studies of DNal (2’)7 ACTH1-17 indicate that the amino acid residues 15, 16 and 17 in NDNal (2’)7-ACTH1-17 are crucial for hMC3R and hMC4R activation. Substitutions of these amino acid residues reduced or abolished agonist activity at hMC3R and hMC4R. Conformational studies revealed a new β-turn (-Arg8-Trp9-Gly10-Lys11-) in NDNal (2’)7-ACTH1-17, compared to the β-turn like structure at NDP-α-MSH (–His6-DPhe7-Arg8-Trp9-). Our results suggest that NDP-α-MSH and NDNal (2’)7-ACTH1-17 does not share the same binding site; highly basic C terminal fragment Lys15-Lys16-Arg17 of NDNal (2’)7-ACTH1-17 induced a new β-turn and this shift contributed the selective agonist activity at hMC3R and hMC4R.
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7.3
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