肖俊宇 教授
蛋白结构与功能研究组
北京大学生命科学学院教授，博士生导师
电话：
E-mail：junyuxiao@pku.edu.cn
1、分泌系统内新型激酶
2、大分子机器的结构与功能研究
1、揭示了“假激酶”POMK作为甘露糖激酶的分子机理
POMK/Sgk196在内质网管腔内磷酸化肌萎缩蛋白聚糖（dystroglycan）上的一个甘露糖分子。有趣的是，POMK在很长时间内被认为是一个“假激酶”，因为从蛋白序列上分析，它缺少很多传统意义上激酶所必需的活性残基。我们解析了POMK与三糖底物以及镁离子、ADP和三氟化铝复合体的高分辨率晶体结构。该结构模拟了POMK激酶反应的过渡状态，也揭示了POMK由位于非典型位置上的催化残基组成的独特活性中心。底物三糖分子由POMK的一个表面凹槽所识别。疾病突变破坏POMK 的结构，导致其功能丧失。
2、揭示了假激酶Fam20A的独特结构和反转颠倒的ATP结合方式
Fam20A蛋白是Fam20C在人体中的一个旁系同源蛋白。二者在序列上有超过60%的同源性。Fam20A基因的突变引起人体牙齿和肾脏发育的疾病，包括“釉质发育不全”和“牙釉质肾综合症”。通过生物信息学、生物化学和结构生物学的方法，我们与合作者发现Fam20A是一个进化上保守的、但没有激酶活性的假激酶，它的真正功能是作为Fam20C的调节因子。Fam20A能够和Fam20C在体内形成稳定的蛋白复合体，并激活Fam20C的激酶活性。我们进一步解析了Fam20A自身和Fam20A-ATP复合物的晶体结构。结果显示，和Fam20C相比，Fam20A拥有一个独特的二硫键骨架结构。一段Fam20A特异的插入环调控此骨架形成。由mRNA 非正常剪切造成的该插入环的缺失，会影响 Fam20A 的结构稳定性，引发牙釉质发育不良。
3、揭示了植物乙烯形成酶ACO2被小分子抑制剂调控的分子基础
在农业生产中，乙烯扮演着非常重要的角色。作为一种植物激素，它参与调控植物生长发育中许多过程，包括叶片衰老和果实成熟。也因如此，乙烯会缩短很多水果和花卉的保质期，造成农业和插花工业的巨大损失。特效而安全的乙烯抑制剂会有助于减轻这些损失。ACC氧化酶（ACO）催化乙烯生物合成途径中的最后一步反应，将ACC分子氧化产生乙烯。郭红卫教授课题组通过化学遗传学手段，鉴定出能特异性抑制ACO活性从而抑制乙烯合成的小分子抑制剂吡嗪甲酸（pyrazinoic acid, POA）和吡啶-2-甲酸（2-picolinic acid，2-PA）。我们进一步解析了拟南芥中ACC氧化酶家族成员ACO2与POA或2-PA复合物的高分辨率晶体结构。晶体结构表明，POA或2-PA均是通过一个金属离子而结合于ACO2的活性中心，从而阻碍了酶与底物ACC的结合，进而抑制了乙烯的产生。
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