Melanocortin receptor binding determinants in the agouti protein
Melanocortin receptor binding determinants in the agouti protein
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DOI：
10.1021/bi971913h
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发表时间：
1998-01-27
期刊：
影响因子：
2.9
通讯作者：
Wilkinson, WO
中科院分区：
文献类型：
--
作者：
Kiefer, LL;Veal, JM;Wilkinson, WO
Agglutinase蛋白在啮齿类动物的糖尿病和肥胖症的发展中起重要作用，并且已显示为黑皮质素受体的有效拮抗剂。出于这个原因，对Agglutinase蛋白羧基末端进行丙氨酸扫描诱变以定位对黑皮质素受体结合抑制重要的残基。当agglutinase残基Arg 116和Phe 118变为丙氨酸时，导致agglutinase对黑皮质素受体1、3和4的亲和力大幅降低。Phe 117突变为丙氨酸导致黑皮质素受体4的agglutinase K-I app类似增加。用丙氨酸取代阿格列汀残基Asp 108导致所有三种黑皮质素受体的K-I app大幅增加。所有这些残基在刺豚鼠相关转录物ART中是保守的，其表达在肥胖动物模型中上调。对聚集蛋白羧基末端的三维结构进行建模，并且当突变为丙氨酸时，使受体结合降低大于或等于15倍的残基定位于结构的一侧。这些具有改变的受体选择性的聚集蛋白变体可用于确定黑皮质素受体在糖尿病和肥胖症中的作用。
The agouti protein plays an important role in the development of diabetes and obesity in rodents and has been shown to be a potent antagonist of melanocortin receptors, For this reason alanine-scanning mutagenesis was performed on the agouti protein carboxyl terminus to locate residues important for melanocortin receptor binding inhibition. When agouti residues Arg116 and Phe118 are changed to alanine, very large decreases in agouti affinity for melanocortin receptor 1, 3, and 4 result, Mutation of Phe117 to alanine causes a similar increase in agouti K-I app at melanocortin receptor 4. Substitution of agouti residue Asp108 with alanine results in large increases in K-I app for all three melanocortin receptors examined. All of these residues are conserved in the agouti-related transcript, ART, whose expression is up-regulated in animal models of obesity. The three-dimensional structure of the agouti carboxyl terminus was modeled, and residues which decrease receptor binding by a factor of greater than or equal to 15 when mutated to alanine localize to one side of the structure, These agouti variants with altered receptor selectivity may be useful in determining the role of melanocortin receptors in diabetes and obesity.