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首页> 外文期刊>Biochemistry >High-Resolution NMR Structure of the Chemically-Synthesized melanocortin Receptor Binding Domain AGRP(87-132) of the Agouti-Related Protein
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High-Resolution NMR Structure of the Chemically-Synthesized melanocortin Receptor Binding Domain AGRP(87-132) of the Agouti-Related Protein

机译：刺痛相关蛋白的化学合成的黑皮质素受体结合域AGRP（87-132）的高分辨率NMR结构。

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摘要

the agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin receptors MC3R and MC4R and MC4R found in the hypothalamus and exhibits potent orexigenic (appetite-stimulating) activity. The cysteine-rich C-terminal domain of this protein, corresponding to AGRP(87-132), contains five disulfide bonds and exhibits receptor binding affinity and antagonism equivalent to that of the full-length protein. The three-dimensional structure of this domain has been determined by ~1H NMR at 800 MHz. The first 34 residuues of AGRP(87-132) are well-ordered and contain a three-stranded antiparallel #beta# sheet, where the last two strands form a #beta# hairpin. The relative spatial positioning of the disulfide cross-links demonstrates that the ordered region of AGRP(87-132) adopts the inhibitor cystine knot (ICK) fold previously identified for numerous invertebrate toxins. Interestingly this may be the first example of a mammalian protein assigned to the ICK superfamily. The hairpin's turn region presents a triplet of residues (Arg-Phe-Phe) known to be essential for melanocortin receptor binding. The structure also suggests that AGRP possesses an additional melanocortin-receptor contact region shows little sequence homology to the corresponding region of the agouti protein, which is an MC1R antagonist involved in pigmentation. Consideration of these sequence differences, along with recent experiments on mutant and chimeric melanocortin receptors, allows us to postulate that this loop in the first 16 residues of its C-terminal domain confers AGRP's distinct selectivity for MC3R and MC4R.
机译：刺豚鼠相关蛋白（AGRP）是下丘脑中发现的黑皮质素受体MC3R和MC4R和MC4R的内源性拮抗剂，并具有有效的促食欲（刺激食欲）活性。该蛋白质的富含半胱氨酸的C末端结构域，对应于AGRP（87-132），包含5个二硫键，并表现出与全长蛋白质相当的受体结合亲和力和拮抗作用。该域的三维结构已通过800 MHz的1H NMR确定。 AGRP的前34个残基（87-132）排列整齐，并包含三链反平行的＃beta＃片，最后两股形成＃beta＃发夹。二硫键交联的相对空间定位表明，AGRP（87-132）的有序区域采用了先前为多种无脊椎动物毒素识别的抑制剂胱氨酸结（ICK）折叠。有趣的是，这可能是分配给ICK超家族的哺乳动物蛋白质的第一个例子。发夹的转弯区域存在三重残基（Arg-Phe-Phe），已知这对黑皮质素受体结合必不可少。该结构还表明，AGRP拥有一个额外的黑皮质素受体接触区域，该区域与agouti蛋白的相应区域几乎没有序列同源性，后者是参与色素沉着的MC1R拮抗剂。考虑这些序列差异，以及最近对突变和嵌合黑皮质素受体进行的实验，使我们推测其C端结构域的前16个残基中的该环赋予AGRP对MC3R和MC4R的独特选择性。

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