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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >Mapping the conformational space accessible to BACE2 using surface mutants and cocrystals with Fab fragments, Fynomers and Xaperones
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Mapping the conformational space accessible to BACE2 using surface mutants and cocrystals with Fab fragments, Fynomers and Xaperones

机译：构象空间的映射使用表面突变体和cocrystals BACE2Fab片段,Fynomers Xaperones

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摘要

The aspartic protease BACE2 is responsible for the shedding of the transmembrane protein Tmem27 from the surface of pancreatic β-cells, which leads to inactivation of the β-cell proliferating activity of Tmem27. This role of BACE2 in the control of β-cell maintenance suggests BACE2 as a drug target for diabetes. Inhibition of BACE2 has recently been shown to lead to improved control of glucose homeostasis and to increased insulin levels in insulin-resistant mice. BACE2 has 52% sequence identity to the well studied Alzheimer's disease target enzyme β-secretase (BACE1). High-resolution BACE2 structures would contribute significantly to the investigation of this enzyme as either a drug target or anti-target. Surface mutagenesis, BACE2-binding antibody Fab fragments, single-domain camelid antibody VHH fragments (Xaperones) and Fyn-kinase-derived SH3 domains (Fynomers) were used as crystallization helpers to obtain the first high-resolution structures of BACE2. Eight crystal structures in six different packing environments define an ensemble of low-energy conformations available to the enzyme. Here, the different strategies used for raising and selecting BACE2 binders for cocrystallization are described and the crystallization success, crystal quality and the time and resources needed to obtain suitable crystals are compared.
机译：天冬氨酸的蛋白酶BACE2负责的跨膜蛋白Tmem27脱落表面的胰腺β肽,从而导致失活的β细胞增殖活动Tmem27。β细胞的维护建议BACE2作为药物糖尿病的目标。最近被证明能够改善控制葡萄糖的体内平衡和增加胰岛素在胰岛素抵抗水平老鼠。序列的身份深入研究阿尔茨海默氏症疾病的目标酶β分泌酶(BACE1)。高分辨率BACE2结构贡献显著的调查这种酶作为一个目标或anti-target药物。诱变,BACE2-binding抗体Fab片段,单极骆驼科VHH抗体(Xaperones)和Fyn-kinase-derived SH3碎片域(Fynomers)作为结晶助手获得第一个高分辨率BACE2结构。六种不同的包装环境定义一个可用的低能构象合奏这种酶。提高并选择BACE2绑定共结晶和描述成功结晶,晶体质量和所需的时间和资源来获取合适的晶体进行了比较。

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