Structural Biology of Regulation of Eukaryotic Gene Expression
Regulation of gene expression in eukaryotes is much more complex than in prokaryotes, and occurs at multiple levels or steps including transcription, mRNA exportation, translation and post-translation. This complexity drives the processes of cellular differentiation and morphogenesis, leading to the creation of different cell types in multi-cellular organisms where different types of cells may possess different gene expression profiles although they all share the same genome materials. Transcription is not only regulated by basal and regulatory transcription factors, but is also subjected to epigenetic regulation including covalent modifications of DNA and histones which can modulate the chromatin structure and subsequently activate or silence the transcription of specific genes. After transcription, the mRNA must be processed, matured, and then exported to cytoplasm before it can be translated. The translation process includes regulation of the ribosome machinery mostly at the level of initiation by various signaling pathways such as the mTOR signaling pathway and fidelity control of the protein synthesis by aminoacyl-tRNA synthetases. All of these processes involve numerous proteins and protein complexes with not well-understood functions and mechanisms. As the biological functions of proteins are largely dictated by their three-dimensional structures, a comprehensive structural and functional knowledge of the proteins will not only enhance the understanding of the structure-function relationship of macromolecules and the relevant biological processes, but also provide molecular basis for the discovery and development of new pharmaceuticals for diagnosis and treatment of human diseases.
Our group is interested in the studies of structures, functions, and molecular mechanisms of proteins and protein complexes involved in the regulation of gene expression in eukaryotes, in particular these of significant biological importance and/or related to human diseases. We utilize primarily structural biology in combination with biochemistry, molecular biology, cell biology, and other biological and biophysical methodologies to determine the three-dimensional structures of these proteins and their complexes with small ligands, substrates, and protein partners, and to elucidate the underlying molecular mechanisms of their biological functions. The primary goal of our research works is to understand the basic sciences of biology and in particular the structure-function relationships of proteins and protein complexes. The ultimate goal of our research works is to utilize the gained structural and functional knowledge to understand molecular basis of pathogenesis of human diseases and to develop effective drugs for the treatments of human diseases.
The current ongoing projects focus on the structural and functional studies of: (1) proteins involved in epigenetic regulation of eukaryotic genes, including histone acetyltransferases and deacetylases, histone methyltransferases and demethylases, DNA methyltransferases and demethylases, and transcription factors; (2) proteins involved in important signaling pathways, particularly the mTORC1 signaling pathway and the DNA damage repair pathway; (3) small GTPases and the related signaling pathways, and (4) important human enzymes involved in protein synthesis and nucleic acid metabolism.
Selected publications from 2010 to now (*Corresponding author):
(1) Wenjing Li, Tianlong Zhang, and Jianping Ding* “Molecular basis for the substrate specificity and catalytic mechanism of thymine-7-hydroxylase in fungi”, Nucleic Acids Res., doi: 10.1093/nar/gkv979, Epub Oct 1 (2015).
(2) Shaoqiong Xu$, Tianlong Zhang$, Shiva N. Kompella$, Mengdi Yan, Aiping Lu, Yanfang Wang, Xiaoxia Shao, Chengwu Chi, David J. Adams*, Jianping Ding*, and Chunguang Wang* “Conotoxin aD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors”, Sci. Rep., 5: 14261 (2015). ($Contributed equally)
(3) Qingyu Tang, Caifeng Liu, Chen Zhong, and Jianping Ding* “Crystal structures of Arabidopsis thaliana Nudix hydrolase NUDT7 reveal a previously unobserved conformation”, Mol. Plant, 8: 1557-1559 (2015).
(4) Katie Powis$, Tianlong Zhang$, Nicolas Panchaud, Rong Wang, Claudio De Virgilio*, and Jianping Ding* “Crystal structure of the Ego1-Ego2-Ego3 complex and its role in promoting Rag GTPase-dependent TORC1 signaling”, Cell Res., 25: 1043-59 (2015). ($Contributed equally)
(5) Fang Yu$, Fangyuan He$, Hongyan Yao, Chengyuan Wang, Jianchuan Wang, Jianxu Li, Xiaofeng Qi, Hong-Wei Xue*, Jianping Ding*, and Peng Zhang* “Structural basis of intramitochondrial phosphatidic acid transport mediated by the Ups1-Mdm35 complex”, EMBO Rep., 16: 813-823 (2015). ($Contributed equally)
(6) Lun Zhang, Jianchuan Wang, Li Hou, Pengrong Cao, Li Wu, Qiansen Zhang, Huaiyu Yang, Yi Zhang*, Jianping Ding* and Jia Li* “Functional role of histidine in the conserved His-x-Asp motif in the catalytic core of protein kinases”, Sci. Rep., 5: 10115 (2015).
(7) Benshang Li, Hui Li, Yun Bai, Renate Kirschner-Schwabe, Jun J Yang, Yao Chen, Gang Lu, Gannie Tzoneva, Xiaotu Ma, Tongmin Wu, Wenjing Li, Haisong Lu, Lixia Ding, Huanhuan Liang, Xiaohang Huang, Minjun Yang, Lei Jin, Hui Kang, Shuting Chen, Alicia Du, Shuhong Shen, Jianping Ding, Hongzhuan Chen, Jing Chen, Arend von Stackelberg, Longjun Gu, Jinghui Zhang, Adolfo Ferrando, Jingyan Tang, Shengyue Wang & Bin-Bing S Zhou “Negative feedback–defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL”, Nature Med., 21: 563-571 (2015).
(8) Zhe Zhang$, Shanshan Wang$, Tong Shen, Jiangye Chen, and Jianping Ding* “Crystal structure of the Rab9A-RUTBC2 RBD complex reveals the molecular basis for the binding specificity of Rab9A with RUTBC2”, Structure, 22, 1408-1420 (2014). ($Contributed equally)
(9) Zilong Zhang, Jian Wu, Wei Lin, Jin Wang, Han Yan, Wei Zhao, Jun Ma, Jianping Ding*, Peng Zhang*, and Guoping Zhao* “Subdomain II of a-isopropylmalate synthase is essential for activity: inferring a mechanism of feedback inhibition”, J. Biol. Chem., 289, 27966-27978 (2014).
(10) Shicheng Zhang, Tianlong Zhang, Minghui Yan, Jianping Ding*, and Jiangye Chen* “Crystal structure of the WOPR-DNA complex and implications for Wor1 function in white-opaque switching of Candida albicans”, Cell Res., 24, 1108-1120 (2014).
(11) Zhe Zhang, Tianlong Zhang, Shanshan Wang, Zou Gong, Chun Tang, Jiangye Chen, and Jianping Ding* “Molecular mechanism for Rabex-5 GEF activation by Rabaptin-5”, eLife, 3, e02687 (2014).
(12) Hui Yang, Tianlong Zhang, Ye Tao, Fang Wang, Liang Tong, and Jianping Ding* “Structural insights into the functions of the FANCM-FAAP24 complex in DNA repair”, Nucleic Acids Res., 41, 10573-10583 (2013).
(13) Shutong Xu, Wenjing Li, Junjun Zhu, Rong Wang, Zheng Li, Guo-Liang Xu, and Jianping Ding* “Crystal structures of isoorotate decarboxylases reveal a novel catalytic mechanism of 5-carboxyl-uracil decarboxylation and shed lights on the search for DNA decarboxylase”, Cell Res., 23, 1296-1309 (2013).
(14) Jianchuan Wang, Chen Zhong, Fang Wang, Fangfang Qu, and Jianping Ding* “Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif”, Biochem. J., 454, 39-47 (2013).
(15) Ke Xu, Minhua Zhang, Qin Zhao, Fang Yu, Hui Guo, Chengyuan Wang, Fangyuan He, Jianping Ding, and Peng Zhang* “Crystal structure of a folate ECF transporter from Lactobacillus brevis”, Nature, 497, 268-271 (2013).
(16) Wei Huang, Zhen Gong, Jian Li, and Jianping Ding* “Crystal structure of Drosophila melanogaster tryptophan 2,3-dioxygenase reveals insights into substrate recognition and catalytic mechanism”, J. Struct. Biol., 181, 291-299 (2013).
(17) Sisi Li, Jiamu Du, Hui Yang, Juan Yin, Jianping Ding*, and Jiang Zhong* “Functional and structural characterization of DNMT2 from Spodoptera frugiperda”, J. Mol. Cell Biol., 5, 64-66 (2013).
(18) Kuan Hu, Meng Zhao, Tianlong Zhang, Manwu Zha, Chen Zhong, Yu Jiang, and Jianping Ding* “Structures of trans-2-enoyl-CoA reductases from Clostridium acetobutulicum and Treponema denticola: insights into the substrate specificity and the catalytic mechanism”, Biochem. J., 449, 79-89 (2013).
(19) Wenjing Li, Chen Zhong, Lei Li, Bingfa Sun, Weiyi Wang, Shutong Xu, Tianlong Zhang, Chunguang Wang, Lan Bao, and Jianping Ding* “Molecular basis of the acetyltransferase activity of MEC-17 towards α-tubulin”, Cell Res., 22, 1707-1711 (2012).
(20) Tianlong Zhang, Marie-Pierre Péli-Gulli, Hui Yang, Claudio De Virgilio, and Jianping Ding* “Ego3 functions as a homodimer to mediate the interaction between Gtr1-Gtr2 and Ego1 in the EGO complex to activate TORC1”, Structure, 20, 2151-2160 (2012).
(21) Manwu Zha, Chen Zhong, Ying Ou, Li Han, Jianchuan Wang, and Jianping Ding* “Crystal structures of human CaMKIa reveal insights into the regulation mechanism of CaMKI”, PLoS One, e44828 (2012).
(22) Hui Yang, Tianlong Zhang, Ye Tao, Lijing Wu, Hong-tao Li, Jin-qiu Zhou, Chen Zhong, and Jianping Ding* “Saccharomyces cerevesiae MHF complex structurally resembles the histones (H3-H4)2 heterotetramer and functions as a heterotetramer”, Structure, 20, 364-370 (2012).
(23) Yufei He, Binzhong Li, Zheng Li, Peng Liu, Yang Wang, Qingyu Tang, Jianping Ding, Yingying Jia, Zhangcheng Chen, Lin Li, Yan Sun, Xiuxue Li, Qing Dai, Chunxiao Song, Kangling Zhang, Chuan He, and Guoliang Xu* “Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA”, Science, 333, 1303-1307 (2011).
(24) Bing Wang, Yingjie Peng, Tianlong Zhang, and Jianping Ding* “Crystal structures and kinetic studies of human kappa class glutathione transferase provide insights into the catalytic mechanism”, Biochem. J., 439, 215-225, (2011).
(25) Bingfa Sun, Shunling Guo, Qingyu Tang, Chen Li, Rong Zeng, Zhiqi Xiong, Chen Zhong, and Jianping Ding* “Regulation of the histone acetyltransferase activity of hMOF via autoacetylation of Lys274”, Cell Res., 21, 1262-1266 (2011). (Featured article)
(26) Shutong Xu, Chen Zhong, Tianlong Zhang, and Jianping Ding* “Structure of human lysine methyltransferase Smyd2 reveals insights into the substrate divergence in Smyd protein”, J. Mol. Cell Biol., 3, 293-300 (2011).
(27) Minyun Zhou, Xianchi Dong, Carsten Baldauf, Hua Chen, Yanfeng Zhou, Timothy A. Springer, Xinping Luo, Chen Zhong, Frauke Gräter, and Jianping Ding* “A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13”, Blood, 117, 4623-4631 (2011).
(28) Shutong Xu, Jian Wu, Bingfa Sun, Chen Zhong, and Jianping Ding* “Structural and biochemical studies of human lysine methyltransferase Smyd3 reveal the important functional roles of its post-SET and TPR domains and the regulation of its activity by DNA binding”, Nucleic Acids Res., 39, 4438-4449 (2011).
(29) Yuanyuan Chang, Jian Wu, Xiajing Tong, Jinqiu Zhou, and Jianping Ding* “Crystal structure of the catalytic core of Saccharomyces cerevesiae histone demethylase Rph1: insights into the substrate specificity and catalytic mechanism”, Biochem. J., 433, 295-302 (2011).
(30) Bei Yang, Chen Zhong, Yingjie Peng, Zheng Lai, and Jianping Ding* “Molecular mechanisms of “off-on switch” of activities of human IDH1 by tumor-associated mutation R132H”, Cell Res., 20, 1188-1200 (2010).
(31) Hui Yang, Jiamu Du, Jianchuan Wang, Chen Zhong, Dapeng Zhang, Huaizu Guo, Yajun Guo, and Jianping Ding* “Structural basis of the immunosuppressive mechanism of therapeutic antibody daclizumab”, Cell Res., 20, 1361-1371 (2010).
(32) Minyun Zhou, Xianchi Dong, Ning Shen, Chen Zhong, and Jianping Ding* “Crystal structure of Saccaromyces cerevisae tryptophanyl-tRNA synthetase: new insights into the mechanism of tryptophan activation and implications for anti-fungal drug design”, Nucleic Acids Res., 38, 3399-3413 (2010).
(33) Bo Zhou, Shanshan Wang, Luxia Xu, Feilong Meng, Yaoji Xuan, Yimin Duan, Jianyong Wang, Hao Hu, Xianchi Dong, Jianping Ding, and Jinqiu Zhou* “SWR1 complex poises heterochromatin boundaries for anti-silencing activity propagation”, Mol. Cell Biol., 30, 2391-2400 (2010).
(34) Mingliang Zhang, Xiajing Tong, Xiaohong Fu, Bo O Zhou, Jianyong Wang, Xinhua Liao, Qianjin Li, Ning Shen, Jianping Ding, and Jinqiu Zhou* “Yeast telomerase subunit Est1p has guanine quadruplex–promoting activity that is required for telomere elongation”, Nat. Struct. Mol. Biol., 17, 202-209 (2010).
(35) Xianchi Dong, Minyun Zhou, Chen Zhong, Ning Shen, Bei Yang, and Jianping Ding* “Crystal structure of P. Horikoshi tryptophanyl-tRNA synthetase and structure-based phylogenetic analysis suggest an archaeal origin of tryptophanyl-tRNA synthetases”, Nucleic Acids Res., 38, 1401-1412 (2010).
(36) Jiamu Du, Hui Yang, Dapeng Zhang, Jianchuan Wang, Huaizu Guo, Baozhen Peng, Yajun Guo, and Jianping Ding* “Structural basis for the blockage of IL-2 signaling by therapeutic antibody Basiliximab”, J. Immunol., 184, 1361-1368 (2010).
Education Background & Academic Experience
Jianping Ding, Ph.D. B.S., Nanjing University, 1982; M.S., Zhongshan University, 1984; Ph.D., Fudan University, 1987. 11/1987-6/1989, Postdoctoral Associate, Shanghai Institute of Ceramics, Chinese Academy of Sciences; 7/1989-8/1991, Research Fellow of the Alexander von Humboldt Foundation, Institute for Crystallography, Free University of Berlin, Germany; 9/1991-1/2001, Assistant/Associate Research Professor, Rutgers University Department of Chemistry, and Senior Research Scientist, Center for Advanced Biotechnology and Medicine, Rutgers University, USA; 11/2000-Present, Professor, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences.