Chimeras of the agouti-related protein: Insights into agonist and antagonist selectivity of melanocortin receptors
Chimeras of the agouti-related protein: Insights into agonist and antagonist selectivity of melanocortin receptors
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DOI：
10.1016/j.peptides.2004.12.036
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发表时间：
2005-10-01
期刊：
影响因子：
3
通讯作者：
Millhauser, GL
中科院分区：
文献类型：
--
作者：
Jackson, PJ;Yu, B;Millhauser, GL
特异性黑皮质素受体MC 3R和MC 4 R与代谢和体重控制直接相关。这些受体被肽激素α-MSH激活，并被刺豚鼠相关蛋白（AGRP）拮抗。尽管a-MSH广泛地作用于MCR家族的大多数成员（MC 2 R除外），但AGRP仅对MC 3R和MC 4 R具有高度特异性。AGRP是约100个氨基酸的复合配体。在AGRP中，MCR识别和拮抗作用定位于34个残基的富含半胱氨酸的结构域，该结构域采用抑制剂胱氨酸结（ICK）折叠。对应于该结构域的氧化折叠肽，称为mini-AGRP，对MC 3R和MC 4 R表现出完全的拮抗剂功能和选择性。在这里，我们研究了一系列嵌合体蛋白的基础上的mini-AGRP支架。将衍生自肽激动剂的氨基酸序列移植到参与受体识别的mini-AGRP活性环中，目的是产生对MC 3R和MC 4 R特异性的基于ICK的激动剂。几种构建体确实表现出有效的激动剂活性;然而，对于所有嵌合体，受体选择性显著改变。药理学数据表明，嵌合体不通过天然AGRP样接触与MC受体相互作用。解释数据的模型表明，MC受体内的激动剂与拮抗剂结合表面仅部分重叠。此外，结合口袋的可及性是高度受体特异性的，MC 3R对配体改变的耐受性最低。(c)2005年爱思唯尔公司All rights reserved.
The specific melanocortin receptors, MC3R and MC4R, are directly linked to metabolism and body weight control. These receptors are activated by the peptide hormone alpha-MSH and antagonized by the agouti-related protein (AGRP). Whereas a-MSH acts broadly on most members of the MCR family (with the exception of MC2R), AGRP is highly specific for only MC3R and MC4R. AGRP is a complex ligand of approximately 100 amino acids. Within AGRP, MCR recognition and antagonism is localized to a 34 residue, cysteine-rich domain that adopts an inhibitor cystine knot (ICK) fold. An oxidatively folded peptide corresponding to this domain, referred to as mini-AGRP, exhibits full antagonist function and selectivity for MC3R and MC4R. Here we investigate a series of chimera proteins based on the mini-AGRP scaffold. Amino acid sequences derived from peptide agonists are grafted into the mini-AGRP active loop, implicated in receptor recognition, with the goal of producing ICK based agonists specific for MC3R and MC4R. Several constructs indeed exhibited potent agonist activity; however, with all chimeras, receptor selectivity is significantly altered. Pharmacologic data indicate that the chimeras do not interact with MC receptors through native AGRP like contacts. A model to explain the data suggest that there is only partial overlap of the agonist versus antagonist binding surfaces within MC receptors. Moreover, accessibility to the binding pocket is highly receptor specific with MC3R being the least tolerant of ligand alterations. (c) 2005 Elsevier Inc. All rights reserved.