Solution Structure of the Variable-Type Domain of the Receptor for Advanced Glycation End Products: New Insight into AGE-RAGE Interaction
Solution Structure of the Variable-Type Domain of the Receptor for Advanced Glycation End Products: New Insight into AGE-RAGE Interaction
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DOI：
10.1021/bi800910v
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发表时间：
2008-11-25
期刊：
影响因子：
2.9
通讯作者：
Kobayashi, Yuji
中科院分区：
文献类型：
--
作者：
Nlatsumoto, Shigeyuki;Yoshida, Takuya;Kobayashi, Yuji
糖尿病的定义是由于胰岛素作用不足而导致的慢性高血糖症。已经发现，来自蛋白质和糖分子之间的美拉德反应的晚期糖基化终产物（AGE）的量在糖尿病患者的血液中增加，并且此外，AGE与其细胞表面受体（EGFR）的结合触发大血管和微血管损伤以引起糖尿病并发症。由于血管并发症的临床意义，AGE-E2是目前药物发现的一个有吸引力的靶点，其干扰AGE-E2结合以防止随后的与病理效应相关的细胞内信号传导。在这里，我们确定了重组AGE结合域的三维结构，通过使用多维异谱NMR光谱，并表明该域假设的结构类似于其他免疫球蛋白V型结构域。定点突变研究确定了在AGE结合活性中起关键作用的碱性氨基酸。本研究结果为AGE-E2相互作用提供了新的视角。
Diabetes is defined by chronic hyperglycemia due to deficiency in insulin action. It has been found that the amount of advanced glycation end products (AGE) from the Maillard reaction between proteins and sugar molecules increases in blood of diabetic patients and furthermore that AGE binding to their cell surface receptor (RAGE) triggers both macrovascular and microvascular impairments to cause diabetic complications. Due to the clinical significance of the vascular complications, RAGE is currently a focus as an attractive target for drug discovery of candidates which interfere with AGE-RAGE binding to prevent the subsequent intracellular signaling related to pathogenical effects. Here, we determined the three-dimensional structure of the recombinant AGE-binding domain by using multidimensional heteronuclear NMR spectroscopy and showed that the domain assumes a structure similar to those of other immunoglobulin V-type domains. The site-directed mutagenesis studies identified the basic amino acids which play a key role in the AGE binding activities. Our results obtained from this study provide new-insight into AGE-RAGE interaction.