医药微生物技术

武大雷

教授
博士/硕士生导师
0532-58631508
个人简介 科研项目 学术论文 其他介绍

教育背景

1999.9-2003.7,山东大学生命科学学院,生物技术学士

2003.9-2008.7,中科院上海药物研究所,药物设计博士


工作经历

2008.8-2011.7,美国加州大学戴维斯分校,博士后

2011.8-2016.8,美国桑福德伯纳姆医学研究所,博士后

2016.9-至今,山东大学微生物技术研究院,教授


研究方向

关键词:分子药理学、结构生物学、化学生物学

本课题组专注于研究重大疾病相关的靶标蛋白。目前重点研究“类核受体”转录因子——bHLH-PAS(basic helix-loop-helix-PER-ARNT-SIM)家族,它们与很多人类疾病密切相关,而且普遍含有小分子配体结合口袋,因此是继核受体之后第二个可作为潜在药物靶标的转录因子家族。一方面综合利用多种实验方法,研究这些蛋白的结构和功能,并揭示蛋白和配体的相互作用,以及配体调控蛋白活性的分子机理;另一方面通过设计和搭建多种化合物筛选体系,发现新的靶向小分子,并进一步通过计算模拟和结构改造等手段,获得活性更好的新药先导化合物。

此外在合成生物学领域,通过与多个课题组合作,共同研究微生物及植物中参与各种合成路径的关键酶类,通过解析其蛋白结构,特别是酶与底物的复合物结构,揭示底物选择性等催化机理,为酶的定向改造提供关键信息。

相关研究成果先后以共同通讯或第一作者发表在Nature、Nature Chemical Biology、Nature Communications、eLife等国际学术期刊上。迄今共发表SCI论文39篇,谷歌学术h-index值24。


科研项目

10.基于结构生物学的药物发现和作用机理研究,山东省自然科学基金杰出青年基金项目,2022/1-2024/12,主持

9.缺氧诱导因子HIF-3α的靶向分子发现和作用机制研究,国家自然科学基金面上项目,2022/1-2025/12,主持

8.“类核受体”转录因子的新靶向分子发现,新药研究国家重点实验室开放课题,2021/5-2022/5,主持

7.山东大学杰出中青年学者学科建设经费,2021/1-2025/12,主持

6. 山东省泰山学者青年专家计划,2020/1-2024/12,主持

5. 致病微生物III型分泌系统结构与功能的研究,国家重点研发计划(政府间国际科技创新合作重点专项),2019/11-2022/10,参与

4. 中德合作项目-亥姆霍兹国际实验室经费,2019/1-2023/12,参与

3. 介导微生物和宿主间信号传递的芳香烃受体AHR的结构和功能研究,国家自然科学基金青年基金项目,2018/1-2020/12,主持

2. 神经转录因子NPAS4的结构和功能研究,江苏省基础研究计划青年基金(山东大学苏州研究院),2017/7-2020/6,主持

1. 山东大学齐鲁青年学者学科建设经费,2016/9-2021/9,主持

发表论文

39. Ma L, Li F, Zhang X, Chen H, Huang Q, Su J, Liu X, Sun T, Fang B, Liu K, Tang D,Wu D, Zhang W, Du L, Li S. Development of MEMS directed evolution strategy for multiplied throughput and convergent evolution of cytochrome P450 enzymes.Sci China Life Sci. 2021 Aug 31. Online ahead of print.

38. Qian M, Liu J, Zhao D, Cai P, Pan C, Jia W, Gao Y, Zhang Y, Zhang N, Zhang Y, Zhang Q,Wu D, Shan C, Zhang M, Schnabl B, Yang S, Shen X, Wang L. Aryl Hydrocarbon Receptor Deficiency in Intestinal Epithelial Cells Aggravates Alcohol-Related Liver Disease.Cell Mol Gastroenterol Hepatol. 2021, Aug 25. Online ahead of print.

37. Gao C, Xu Y, Liang Z, Wang Y, Shang Q, Zhang S, Wang C, Ni M,Wu D, Huang Z, Pang T. A novel PGAM5 inhibitor LFHP-1c protects blood-brain barrier integrity in ischemic stroke. Acta Pharm Sin B. 2021, 11: 1867-1884.

36. Tie L*, Xiao H*, Wu D*, Yang Y, Wang P. A brief guide to good practices in pharmacological experiments: Western blotting. Acta Pharmacol Sin. 2021, 42: 1015-1017.(*共同通讯作者)

35. Zhong L, Diao X, Zhang N, Li F, Zhou H, Chen H, Bai X, Ren X, Zhang Y*, Wu D*, Bian X*. Engineering and elucidation of the lipoinitiation process in nonribosomal peptide biosynthesis. Nat Commun. 2021, 12: 296.(*共同通讯作者)[入选“有机化学和化学生物学”领域焦点论文]

34. Dahlem C, Kado SY, He Y, Bein K, Wu D, Haarmann-Stemmann T, Kado NY, Vogel CFA. AHR signaling interacting with nutritional factors regulating the expression of markers in vascular inflammation and atherogenesis. Int J Mol Sci. 2020, 21: 8287.

33. Jiang K, Zhang Y, Chen Z, Wu D, Cai J, Gao X. Structural and functional insights into the C-terminal fragment of insecticidal Vip3A toxin of Bacillus thuringiensis. Toxins (Basel). 2020, 12: 438.

32. Xu M, Xu HH, Lin Y, Sun X, Wang LJ, Fang ZP, Su XH, Liang XJ, Hu Y, Liu ZM, Cheng Y, Wei Y, Li J, Li L, Liu HJ, Cheng Z, Tang N, Peng C, Li T, Liu T, Qiao L, Wu D, Ding YQ, Zhou WJ. LECT2, a ligand for Tie1, plays a crucial role in liver fibrogenesis. Cell. 2019, 178: 1478-1492. [获得F1000Prime推荐]

31. Wu D*, Su X, Lu J, Li S, Hood BL, Vasile S, Potluri N, Diao X, Kim Y, Khorasanizadeh S, Rastinejad F*. Bidirectional modulation of HIF-2 activity through chemical ligands. Nat Chem Biol. 2019, 15: 367-376. (*共同通讯作者)[获得F1000Prime推荐]

30. Chandra V#, Wu D#, Li S, Potluri N, Kim Y, Rastinejad F. The quaternary architecture of RARβ-RXRα heterodimer facilitates domain-domain signal transmission. Nat Commun.2017, 8: 868.(#共同第一作者)

29. Wu D, Rastinejad F. Structural characterization of mammalian bHLH-PAS transcription factors. Curr Opin Struct Biol. 2017, 43: 1-9.

28. Smith SH, Jayawickreme C, Rickard DJ, Nicodeme E, Bui T, Simmons C, Coquery CM, Neil J, Pryor WM, Mayhew D, Rajpal DK, Creech K, Furst S, Lee J, Wu D, Rastinejad F, Willson TM, Viviani F, Morris DC, Moore JT, Cote-Sierra J. Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans. J Invest Dermatol. 2017, 137: 2110-2119.

27. Wu D, Su X, Potluri N, Kim Y, Rastinejad F. NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors. eLife. 2016, 5: e18790.

26. Vogel CF, Charrier JG,Wu D, McFall AS, Li W, Abid A, Kennedy IM, Anastasio C. Physicochemical properties of iron oxide nanoparticles that contribute to cellular ROS-dependent signaling and acellular production of hydroxyl radical. Free Radic Res. 2016, 50: 1153-1164.

25. Vogel CF, Chang WL, Kado S, McCulloh K, Vogel H, Wu D, Haarmann-Stemmann T, Yang G, Leung PS, Matsumura F, Gershwin ME. Transgenic overexpression of aryl hydrocarbon receptor repressor (AhRR) and AhR-mediated induction of CYP1A1, cytokines, and acute toxicity. Environ Health Perspect. 2016, 124: 1071-1083.

24. Wu D, Potluri N, Lu J, Kim Y, Rastinejad F. Structural integration in hypoxia-inducible factors. Nature. 2015, 524: 303-308. [在Nature同期News&Views栏目中被特别介绍,并获得F1000Prime推荐]

23. Vogel CF, Khan EM, Leung PS, Gershwin ME, Chang WL, Wu D, Haarmann-Stemmann T, Hoffmann A, Denison MS. Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-κB. J Biol Chem. 2014, 289: 1866-1875.

22. Wu D, Potluri N, Kim Y, Rastinejad F. Structure and dimerization properties of the aryl hydrocarbon receptor PAS-A domain. Mol Cell Biol. 2013, 33: 4346-4356. [被编辑选为当期“意义显著”论文之一]

21. Chandra V, Huang P, Potluri N, Wu D, Kim Y, Rastinejad F. Multidomain integration in the structure of the HNF-4α nuclear receptor complex. Nature. 2013, 495: 394-398.

20. Vogel CF, Wu D, Goth SR, Baek J, Lollies A, Domhardt R, Grindel A, Pessah IN. Aryl hydrocarbon receptor signaling regulates NF-κB RelB activation during dendritic-cell differentiation. Immunol Cell Biol. 2013, 91: 568-575.

19. Vogel CF, Garcia J, Wu D, Mitchell DC, Zhang Y, Kado NY, Wong P, Trujillo DA, Lollies A, Bennet D, Schenker MB, Mitloehner FM. Activation of inflammatory responses in human U937 macrophages by particulate matter collected from dairy farms: an in vitro expression analysis of pro-inflammatory markers. Environ Health. 2012, 11: 17.

18. Wu D#, Nishimura N#, Kuo V, Fiehn O, Shahbaz S, Van Winkle L, Matsumura F, Vogel CF. Activation of aryl hydrocarbon receptor induces vascular inflammation and promotes atherosclerosis in apolipoprotein E-/- mice. Arterioscler Thromb Vasc Biol. 2011, 31: 1260-1267. (#共同第一作者)[被编辑在同期社论中推荐]

17. Wu D, Wong P, Li W, Vogel CF, Matsumura F. Suppression of WIF-1 through promoter hypermethylation causes accelerated proliferation of the aryl hydrocarbon receptor (AHR) overexpressing MCF10AT1 breast cancer cells. Toxicology. 2011, 285: 97-103.

16. Wu D, Li W, Lok P, Matsumura F, Vogel CF. AhR deficiency impairs expression of LPS-induced inflammatory genes in mice. Biochem Biophys Res Commun. 2011, 410: 358-363.

15. Fujisawa Y, Li W, Wu D, Wong P, Vogel C, Dong B, Kung HJ, Matsumura F. Ligand-independent activation of the aryl hydrocarbon receptor by ETK (Bmx) tyrosine kinase helps MCF10AT1 breast cancer cells to survive in an apoptosis-inducing environment. Biol Chem. 2011, 392: 897-908.

14. Vogel CF, Li W, Wu D, Miller JK, Sweeney C, Lazennec G, Fujisawa Y, Matsumura F. Interaction of aryl hydrocarbon receptor and NF-κB subunit RelB in breast cancer is associated with interleukin-8 overexpression. Arch Biochem Biophys. 2011, 512: 78-86.

13. Dong B, Cheng W, Li W, Zheng J, Wu D, Matsumura F, Vogel CF. FRET analysis of protein tyrosine kinase c-Src activation mediated via aryl hydrocarbon receptor. Biochim Biophys Acta. 2011, 1810: 427-431.

12. Sciullo EM, Vogel CF, Wu D, Murakami A, Ohigashi H, Matsumura F. Effects of selected food phytochemicals in reducing the toxic actions of TCDD and p,p'-DDT in U937 macrophages. Arch Toxicol. 2010, 84: 957-966.

11. Li W, Vogel CF, Wu D, Matsumura F. Non-genomic action of TCDD to induce inflammatory responses in HepG2 human hepatoma cells and in liver of C57BL/6J mice. Biol Chem.2010, 391: 1205-1219.

10. Han C, Hu T, Wu D, Qu S, Zhou J, Ding J, Shen X, Qu D, Jiang H. X-ray crystallographic and enzymatic analyses of shikimate dehydrogenase from Staphylococcus epidermidis. FEBS J. 2009, 276: 1125-1139.

9. Wu D, Kong Y, Han C, Chen J, Hu L, Jiang H, Shen X. D-Alanine-D-alanine ligase as a new target for the flavonoids quercetin and apigenin. Int J Antimicrob Agents. 2008, 32: 421-426.

8. Wu D, Zhang L, Kong Y, Du J, Chen S, Chen J, Ding J, Jiang H, Shen X. Enzymatic characterization and crystal structure analysis of the D-alanine-D-alanine ligase from Helicobacter pylori. Proteins. 2008, 72: 1148-1160.

7. Wu D, Hu T, Zhang L, Chen J, Du J, Ding J, Jiang H, Shen X. Residues Asp164 and Glu165 at the substrate entryway function potently in substrate orientation of alanine racemase from E. coli: Enzymatic characterization with crystal structure analysis. Protein Sci. 2008, 17: 1066-1076.

6. Hu T#, Wu D#, Chen J, Ding J, Jiang H, Shen X. The catalytic intermediate stabilized by a "down" active site loop for diaminopimelate decarboxylase from Helicobacter pylori. Enzymatic characterization with crystal structure analysis. J Biol Chem. 2008, 283: 21284-21293.(#共同第一作者)

5. Kong Y#, Wu D#, Bai H, Han C, Chen J, Chen L, Hu L, Jiang H, Shen X. Enzymatic characterization and inhibitor discovery of a new cystathionine γ-synthase from Helicobacter pylori. J Biochem. 2008, 143: 59-68.(#共同第一作者)

4. Zhang L#, Kong Y#, Wu D#, Zhang H, Wu J, Chen J, Ding J, Hu L, Jiang H, Shen X. Three flavonoids targeting the beta-hydroxyacyl-acyl carrier protein dehydratase from Helicobacter pylori: crystal structure characterization with enzymatic inhibition assay. Protein Sci. 2008, 17: 1971-1978.(#共同第一作者)

3. Kong D, Zhu W, Wu D, Shen X, Jiang H. Comparison of three 3D-QSAR methods using a novel class of MURF inhibitors. J Theor Comput Chem. 2007, 6: 63-80.

2. Cai J, Han C, Hu T, Zhang J, Wu D, Wang F, Liu Y, Ding J, Chen K, Yue J, Shen X, Jiang H. Peptide deformylase is a potential target for anti-Helicobacter pylori drugs: reverse docking, enzymatic assay, and X-ray crystallography validation. Protein Sci. 2006, 15: 2071-2081.

1. Luo H, Wu D, Shen C, Chen K, Shen X, Jiang H. Severe acute respiratory syndrome coronavirus membrane protein interacts with nucleocapsid protein mostly through their carboxyl termini by electrostatic attraction. Int J Biochem Cell Biol. 2006, 38: 589-599.

学术兼职

《药学学报》中英文刊青年编委

中国药理学会生化与分子药理专业委员会委员

中国药理学会海洋药物药理专业委员会委员

全国卫生产业企业管理协会精准医疗分会理事

山东省药理学会第六届理事会理事


奖励荣誉

2021年 山东大学微生物技术研究院“优秀共产党员”

2020年 山东大学微生物技术研究院“科研之星”

2019年 山东省“泰山学者青年专家”