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基于基因编码的片段发现了用于碳水化合物结合蛋白的糖联体

Simon Ng¹, Edith Lin¹, Pavel I Kitov¹

¹†Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.

Journal of the American Chemical Society

|April 11, 2015

概括

基于基因编码片段的发现 (GE-FBD) 快速识别碳水化合物识别域 (CRD) 的抑制剂. 这种方法产生了一种Man-WYD,它对像ConA这样的曼诺结合蛋白具有很高的亲和力和特异性.

科学领域:

生物化学生物化学
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

碳水化合物识别域 (CRD) 对生物过程至关重要.
鉴定CRDs的竞争性抑制剂是一项挑战.
现有的抑制剂发现方法通常是缓慢和低效的.

研究的目的:

开发一种快速有效的方法来发现CRDs的竞争性抑制剂.
用新方法验证使用新方法识别的抑制剂的疗效和特异性.
为了深入了解模仿碳水化合物的配体的结合机制.

主要方法:

基因编码基于碎片的发现 (GE-FBD) 使用菌体显示.
选择糖来识别协同作用的基因.
使用生物物理方法和莱克阵列验证亲和力和特异性.
用X射线晶体学来确定蛋白质-连接体复杂结构.

主要成果:

GE-FBD成功地从10^8个糖的图书馆中识别出一个共识动机 (Man-WYD).
与MeMan相比,合成Man-WYDLF的亲和力提高了40-50倍.
人类WYD衍生物证明了与曼诺结合蛋白 (ConA,LcH,PSA) 的特定结合.
X射线结构显示了相同的CRD对接,但对Man-WYD和碳水化合物连接体有不同的CRD外结合模式.

结论:

GE-FBD是一种强大的方法,可以加速寻找CRD抑制剂.
配体可以在功能上模仿碳水化合物,提供新的治疗策略.
已识别的Man-WYD代表了针对曼诺结合蛋白的有希望的头.

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