赌博app

性别: 男
工作电话: 020-39332943
电子邮件: [email protected]
职称: 教授
导师类型: 博士生导师
学历: 博士
学科方向:
071010-生物化学与分子生物学

 

研究方向

蛋白质结构与功能关系

酶催化的分子机制

蛋白-蛋白，蛋白-核酸互作的结构基础

基于生物大分子三维结构的抑制剂设计

具体研究方向：

生物学的中心任务是揭示基因组序列及其编码的蛋白质功能。在后基因组时代，随着越来越多的基因组全序列被测定，生命科学的研究重心由基因转向蛋白质。蛋白质是有机体的重要组成部分，人体各种组织无一不含蛋白质，并依靠其行使多种多样的生理功能。蛋白质的功能由其三维结构决定。众多重大疾病多由致病基因所编码的蛋白质功能发生紊乱引起，大多源于突变引起的蛋白空间结构变化，导致其不能正常发挥其功能。测定和解析这些蛋白质的三维结构，在阐明生命的关键过程、疾病发生的分子机理和基于结构的药物研发中发挥了巨大的作用。

我们采用包括X-射线晶体衍射在内的多种生物物理表征手段，结合生物化学，化学生物学等多学科技术，来研究重要功能蛋白（尤其是核酸结合蛋白）的结构基础。具体研究方向如下：

1. RNA 的加工修饰

所有RNA 经转录出来后必须经历一系列加工过程才能成为成熟的、具有生理功能的RNA分子，其中包括复杂的核苷酸化学修饰步骤。具有生理活性的RNA分子是基因表达的关键。这些修饰除除维持RNA 固有的二、三级结构及稳定性外，还可提高翻译过程的效率及忠实性。目前人们已鉴定的RNA修饰多达170多种，包括存在于tRNA之上的超修饰 (hypermodification)。据估计，细菌里1%的基因被用于编码RNA修饰酶。除少数修饰被深入研究外，大多数修饰的机制、相关酶类、生物学意义不明。我们试图对相关修饰酶及其与RNA复合物的结构及生化性质的表征，明确其催化机制及体内外功能。过去近10年时间里，课题组解析了多个修饰酶及其数个酶-核酸复合物的共晶结构, 阐明了这些酶对tRNA底物的识别机制；通过多种生物物理手段，研究酶在催化过程中的构象变化，提出催化路径模型，明确其重要的生理功能。

2. DNA的碱基切除修复机制 (BER)

DNA 损伤无时不刻在发生，是诱发机体功能障碍、衰老以及癌症的主要原因。在DNA中，脱氧尿嘧啶dU可能由胞嘧啶脱氨修饰引入，造成转录或复制时 G-to-A的转换突变，从而可能引起编码蛋白质的改变。为此，Base excision repair (简称BER) 修复机制应运而生，而尿嘧啶DNA糖基化酶 (UDG) 是其中最为重要的蛋白，负责识别、切除 dU，形成无碱基位点, 并启动下游修复过程。UDG广泛存在于三界，分为六个家族，催化性质各不相同。在过去20年里，人们对家族1-3研究较多，具有较深认识，但对于家族4-6研究较少，作用方式并不明确。尤其近年来发现的一些具有特殊性质的非经典UDG。课题组系统研究了来自多个家族的UDG酶的结构与生化特征，鉴定与表征了一批具有特殊催化性质的UDG，并提出新的催化机制，完善了人们对UDG酶的认知。

3. 参与表观遗传学的核酸修饰酶类

自从人类基因组图谱绘成，基因的特定功能研究和基于中心法则的表达研究已基本完成，而表观遗传学作为一个蓬勃发展中的研究领域，许多详细机制尚有待深入和系统研究。近年来 RNA 修饰在表观遗传学领域引起了广泛的研究兴趣。其中关于哺乳动物中 mRNA 上最为常见的 N6 -腺苷甲基化修饰（m6A）研究极为活跃，且其异常甲基化模式已经被证明与包括癌症在内的多种人类疾病相关。尽管m6A修饰在哺乳动物中普遍存在，但在原核生物体内却几乎不存在；而是以6mA这种存在于DNA上的修饰取而代之，作为细菌体内的“甲基化-修饰”机制的一部分存在。与之类似，6mA仅在少数真核生物基因组中被检测到（或被认为是实验假象），其生物学意义由于其丰度之低而被人们质疑。因此，6mA/m6A不论从机制、功能还是进化角度都是一个非常值得研究的问题。我们拟/正在研究包括Alkbh1/4、6mA/m6A甲基转移及其脱氨作用多个蛋白的潜在作用机理以及影响基因表达的修饰方式，为进一步明确其生理意义或为将来开发小分子物质进行调节这些途径提供依据。

4. 毒素/抗毒素(TA)系统的拮抗机制及对病原菌状态的调控

毒素-抗毒素系统是广泛存在于细菌和真菌细胞内的一对小型遗传控制元件，与细菌的多项重要生命活动有关。毒素基因编码稳定的蛋白质，多数情况下执行核酸内切酶的功能；抗毒素基因编码稳定性较差的蛋白或者是具有调控功能的RNA，起中和毒素毒性的作用。在应激条件下，毒素表达迅速上调，并以各种RNA为底物进行剪切，使细菌的翻译过程几近停滞。进而抑制细菌各项生命活动甚至使其出现利它性死亡，进入持留状态，并表现出对抗生素耐受，最终使种群获得生存机会。近年来的多项研究表明，包括结核分枝杆菌在内的多种病原菌通过广泛存在于体内的TA系统来介导耐药过程。课题组近年来研究了结核分枝杆菌毒素家族成员 MazEF-mt9/mt1剪切RNA的生化性质, 表征了该毒素与同、异源抗毒素的相互作用，并由此设计了一系列靶向多毒素靶标的多肽，用于抗菌研究。

 

个人经历

谢伟，男，1976年生，赌博app-网络赌博软件 教授，博士生导师。1997年毕业于武汉大学化学系获理学学士学位，2005年毕业于美国伊利诺伊大学香槟城分校（UIUC）生物化学系获生物化学博士学位。2005年9月至2010年2月分别在Scripps 研究所及Salk研究所进行两站博士后研究。2010 年3月作为中山大学百人计划教授引进，从事核酸的修饰、重要功能蛋白的分子机制等生物学问题的研究，近年来以通讯作者身份在Nature chemical biology, Science advances, Nature communications, Nucleic acids research, BMC biology, Chemical communications, JBC, JMB, JVI, Communications biology, Biochemical journal, FEBS journal等国际知名 SCI 期刊发表学术论文40余篇。

 

论文专著

近年发表发表文章 （倒序排列，*：通讯作者；#: 一作)：

1.    Jia, Q., Zeng, H., Li H., Xiao, N., Tang, J., Gao, S., Zhang, J., Xie, W.* (2021) The C-terminal loop of Arabidopsis thaliana guanosine deaminase is essential to catalysis. Chem Commun (Camb) 57(76):9748.doi: 10.1039/d1cc03042f.

2.    Jia, Q., Zeng, H., Zhang, J., Gao, S., Xiao, N., Tang, J., Dong., X.*, Xie, W.* (2021) The Crystal Structure of the Spodoptera litura Chemosensory Protein CSP8. Insects 12, 602. // doi.org/10.3390/insects12070602.

3.    Li, H., Zhang, Y., Guo, Y., Liu, R., Yu, Q., Gong, L., Liu, Z.*, Xie, W.*, Wang, C.*. (2021) ALKBH1 promotes lung cancer by regulating m6A RNA demethylation. Biochem Pharmacol, 189:114284. doi: 10.1016/j.bcp.2020.114284. Epub 2020 Oct 14.

4.    Liu, X., Zhou, J., Ge, R.*, Xie, W.* (2021) Functional and structural investigation of N-terminal domain of the SpTad2/3 heterodimeric tRNA deaminase. Comput Struct Biotechnol J. 19:3384-3393.doi: 10.1016/j.csbj.2021.06.008. eCollection 2021.

5.    Chen, R., Zhou, J., Xie, W.* (2021) Mechanistic Insight into the Peptide Binding Modes to Two M. tb MazF Toxins. Toxins (Basel). 13(5):319. doi: 10.3390/toxins13050319.

6.    He, P., Wang, C., Wang, Y., Wang, C., Zhou, C., Cao, D., Li, J., Bushnell, D., Li, Q., Kornberg, R.*, Xie, W.*, Wang, Z*. (2021) A novel AKR1C3 specific prodrug th3424 with potent antitumor activity in liver Cancer. Clin Pharmacol Ther. 110(1):229-237.doi: 10.1002/cpt.2171. Epub 2021 Mar 10.

7.    Jia, Q., Zeng, H., Tu, J., Sun, L., Cao, W., Xie, W.* (2021) Structural insights into an MsmUdgX mutant capable of both crosslinking and uracil excision capability. DNA Repair (Amst), 97:103008.

8.    Liu, X., Chen, R., Sun, Y., Chen, R., Zhou, J., Tian, Q., Tao, X., Zhang, Z., Luo, G., Xie, W.* (2020) Crystal structure of the yeast heterodimeric ADAT2/3 deaminase. BMC Biol, 18(1):189.

9.    Chen, R., Zhou, J., Sun, R., Du, C., Xie, W*. (2020) Conserved conformational changes in the regulation of Mycobacterium tuberculosis MazEF-mt1. ACS Infect Dis. 10;6(7):1783-1795. doi: 10.1021/acsinfecdis.0c00048.

10.    Cao, L., Chen, R., Huang, X., Li, S., Zhang, S., Yang, X., Qin, Z., Kong, W., Xie, W*., Liu, Y.* (2020) Engineering of β-Glucosidase Bgl15 with simultaneously enhanced glucose tolerance and thermostability to improve its performance in high-solid cellulose hydrolysis. J Agric Food Chem, 68(19):5391-5401.doi: 10.1021/acs.jafc.0c01817.

11.    Liu, H., Wu, S., Ran, D., Xie W*. (2020) Structure of a tRNA-specific deaminase with compromised deamination activity. Biochem J, 477(8):1483-1497. doi: 10.1042/BCJ20190858.

12.    Zhang, L., Zhu, L., Qu, W., Wu, F., Hu, M., Xie, W.*., Liu, Z.*, Wang, C.*, (2020) Insight into tartrate inhibition patterns in vitro and in vivo based on cocrystal structure with UDP-glycosyltransferase 2B15, Biochemical Pharmacology, 172:113753.doi: 10.1016/j.bcp.2019.113753.

13.    Liu, X., Cao, L., Zeng J., Liu, Y.*, Xie W.* (2019) Improving the cellobiose-hydrolysis activity and glucose-tolerance of a thermostable β-glucosidase through rational design. International Journal of Biological Macromolecules 136:1052-1059. doi: 10.1016/j.ijbiomac.

14.    Tu, J., Chen, R., Yang, Y., Cao, W., Xie, W.* (2019) Suicide inactivation of the uracil DNA glycosylase UdgX by covalent complex formation. Nature chemical biology, 15:615-622. doi: 10.1038/s41589-019-0290-x.

15.    Jia, Q., Xie, W.* (2019) Alternative conformation induced by substrate binding for Arabidopsis thaliana N6-methyl-AMP deaminase. Nucleic Acids Res. 47, 3233-3243. doi: 10.1093/nar/gkz070.

16.    Chen, R., Tu, J., Tan, Y., Cai, X., Yang, C., Deng, X., Su, B., Ma, S., Liu, X., Ma, P., Du, C., Xie, W.* (2019) Structural and Biochemical Characterization of the Cognate and Heterologous Interactions of the MazEF-mt9 TA System. ACS Infect Dis. 5(8):1306-1316. doi: 10.1021/acsinfecdis.9b00001.

17.    Cao, L.  #, Chen, R. #, Huang X., Qin Z., Kong W., Xie, W.*, and Liu, Y. H*. (2018) Enhancing the Thermostability of Highly Active and Glucose-Tolerant β-Glucosidase Ks5A7 by Directed Evolution for Good Performance of Three Properties, Journal of agricultural and food chemistry 66, 13228-13235. doi: 10.1021/acs.jafc.8b05662.

18.    Yang, J. #, Deng, X. #, Li, Y., Ma, X., Feng, J., Yu, B., Chen, Y., Luo, Y., Wang, X., Chen, M., Fang, Z., Zheng, F., Li, Y., Zhong, Q., Kang. T., Song, L., Xu, R., Zeng, M., Chen, W., Zhang, H., Xie, W. *, Gao, S* (2018) Structure of Schlafen13 reveals a new class of tRNA/rRNA- targeting RNase engaged in translational control, Nat Commun. 9, 1165. doi: 10.1038/s41467-018-03544-x.

19.    Jia Q., Lin Y., Gou X., He L., Shen D., Chen D., Xie W.*, Lu Y.*. (2018) Legionella pneumophila effector WipA, a bacterial PPP protein phosphatase with PTP activity. Acta Biochim Biophys Sin (Shanghai). 50:547-554. doi: 10.1093/abbs/gmy042.

20.    Wang, C. #, Jia, Q. #, Zeng, J., Chen, R., Xie, W.* (2017) Structural insight into the methyltransfer mechanism of the bifunctional Trm5, Science advances, 3:e1700195.

21.    Wu, J., Jia, Q., Wu, S., Zeng, H., Sun, Y., Wang, C., Ge, R*., Xie, W.* (2017) The crystal structure of the Pyrococcus abyssi mono-functional methyltransferase PaTrm5b. Biochemical and biophysical research communications 493, 240-245.

22.    Wang, C., Zeng, J., Xie, W.* (2017) A flexible cofactor-binding loop in the novel arginine methyltransferase Sfm1. FEBS letters 591, 433-441.

23.    Wang, C., Wang, C., Li, Q., Wang, Z.*, Xie, W.* (2017) Crystal structure and thermostability characterization of EV-D68-3Dpol. Journal of virology 91(18). pii: e00876-17. doi: 10.1128/JVI.00876-17.

24.    Pang, P., Yang, Y., Li, J., Wang, Z., Cao, W.*, Xie, W.* (2017) SMUG2 DNA glycosylase from Pedobacter heparinus as a new subfamily of the UDG superfamily. The Biochemical journal 474, 923-938.

25.    Pang, P., Deng, X., Wang, Z., Xie, W.* (2017) Structural and biochemical insights into the 2'-O-methylation of pyrimidines 34 in tRNA. The FEBS journal 284, 2251-2263.

26.    Pang, P., Cao, L. C., Liu, Y. H., Xie, W.*, Wang, Z*. (2017) Structures of a glucose-tolerant beta-glucosidase provide insights into its mechanism. Journal of structural biology 198, 154-162.

27.    Liu, X., Wu, J., Sun, Y., Xie, W.* (2017) Substrate Recognition Mechanism of the Putative Yeast Carnosine N-methyltransferase. ACS chemical biology 12, 2164-2171.

28.    Li, J., Chen, R., Yang, Y., Zhang, Z., Fang, G. C., Xie, W.*, Cao, W.* (2017) An unconventional family 1 uracil DNA glycosylase in Nitratifractor salsuginis. The FEBS journal 284, 4017-4034. doi: 10.1111/febs.14285. [Epub ahead of print]

29.    Chen, R., Tu, J., Liu, Z., Meng, F., Ma, P., Ding, Z., Yang, C., Chen, L., Deng, X., Xie, W.* (2017) Structure of the MazF-mt9 toxin, a tRNA-specific endonuclease from Mycobacterium tuberculosis. Biochemical and biophysical research communications 486, 804-810.

30.    Liu X, Cao L, Xin-jiong Fan, Liu Y*, Xie, W.*, (2016) Engineering of a thermostable esterase Est816 to improve its quorum-quenching activity and the underlying structural basis. Scientific reports, 6:38137.

31.    Wang, C., Jia, Q., Chen, R., Wei, Y., Li, J., Ma, J., Xie, W.* (2016) Crystal structures of the bifunctional tRNA methyltransferase Trm5a. Scientific reports 6:33553.

32.    Liu, X., Zeng J., Chen X., Xie, W.* (2016) Crystal structures of RidA, an important enzyme for the prevention of toxic side products, Scientific reports, 6:30494.

33.    Qin, X., Deng, X., Chen, L., Xie, W.* (2016) Crystal structure of the wild-type human GlyRS bound with tRNAGly in a productive conformation, Journal of molecular biology, 428, 3603-3614. Doi: 10.1016/j.jmb.2016.05.018. [Epub ahead of print].

34.    Zhang, Z., Shen, J., Yang, Y., Li, J., Cao, W., Xie, W.* (2016) Structural basis of substrate specificity in Geobacter metallireducens SMUG1, ACS chemical biology 11, 1729-1736.

35.    Deng, X., Qin, X., Chen, L., Jia, Q., Zhang, Y., Zhang, Z., Lei, D., Ren, G., Zhou, Z., Wang, Z., Li, Q., Xie, W.* (2016) Large conformational changes of insertion 3 in human glycyl-tRNA synthetase (hGlyRS) during catalysis, J Biol Chem, 291, 5740-5752. DOI: 10.1074/jbc.M115.679126.

36.    Zhang, Z., Jia, Q., Zhou, C., Xie, W.* (2015) Crystal structure of E. coli endonuclease V, an essential enzyme for deamination repair, Scientific reports 5, 12754.

37.    Wang, C., Guo, Y., Tian, Q., Jia, Q., Gao, Y., Zhang, Q., Zhou, C., Xie, W.* (2015) SerRS-tRNASec complex structures reveal mechanism of the first step in selenocysteine biosynthesis, Nucleic acids research 43, 10534-10545.

38.    Tian, Q., Wang, C., Liu, Y., Xie, W.* (2015) Structural basis for recognition of G-1-containing tRNA by histidyl-tRNA synthetase, Nucleic acids research 43, 2980-2990.

39.    Cao, L. C., Chen, R., Xie, W.*, Liu, Y.*. (2015) Enhancing the Thermostability of Feruloyl Esterase EstF27 by Directed Evolution and the Underlying Structural Basis, Journal of agricultural and food chemistry 63, 8225-8233.  

40.    Zhang, Z., Hao, Z., Wang, Z., Li, Q., Xie, W.* (2014) Structure of human endonuclease V as an inosine-specific ribonuclease, Acta Crystallogr D Biol Crystallogr 70, 2286-2294.

41. Qin, X., Hao, Z., Tian, Q., Zhang, Z., Zhou, C., Xie, W.* (2014) Cocrystal structures of glycyl-tRNA synthetase in complex with tRNA suggest multiple conformational states in glycylation, J Biol Chem 289, 20359-20369.