Education

Research Experience

Research Interests

Our research focuses on drug targets related to major diseases, such as transcription factor proteins in human body, and key enzymes and virulence factors in pathogenic microorganisms.

On one hand, we use techniques of structural biology and molecular pharmacology, to study the structure and function of these proteins, and to reveal the interaction between proteins and ligands, as well as the molecular mechanism of ligands regulating protein function. On the other hand, we aim to discover new targeted small-molecules, through the design and construction of a variety of compound screening systems, and to obtain new lead compounds with better activity, by means of computational simulation and structural modification.

Research Projects

One major set of ongoing projects are about the so-called "nuclear receptor-like" transcription factors, the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, which are closely related to many human diseases and generally all contain ligand binding pockets. Therefore, they are the second family of transcription factors that can be explored as potential drug targets after nuclear receptors.

The hypoxia-inducible factors (HIFs) within the bHLH-PAS family function as sensors of low oxygen stress and respond to hypoxia by regulating genes in erythropoiesis, angiogenesis and cellular metabolism. The HIF proteins function as obligate heterodimers consisting of oneαsubunit and ARNT (also called HIF-β).We solved the complex structures of HIF-αand ARNT proteins, which reveal the dimer formation mode, DNA recognition manner and ligand binding sites. We also for the first time discovered the small-molecule agonists of HIF-2α, and revealed the molecular mechanism of bi-directional regulation of transcriptional activity by allosteric effects, providing an important basis for the design of new anticancer (antagonists) or anti-anemia (agonists) drugs targeting HIF-2αprotein.

Representative Publications

Ⅰ.Field of structural and functional studies of transcription factor target proteins and targeted molecular discovery

13. Zhang M, Guo Y, Diao X, Guo M, Teng H, Sun X, Zhuang J, Song C, Xie X,Wu D. Molecular mechanism of the crosstalk between glucocorticoid receptor (GR) and hypoxia-inducible factor 3α(HIF-3α) pathways.Mar Life Sci Technol. 2025, Jun 4. (Independent Corresponding Author)

12. Diao X, Shang Q, Guo M, Huang Y, Zhang M, Chen X, Liang Y, Sun X, Zhou F, Zhuang J, Liu SJ, Vogel CFA, Rastinejad F,Wu D. Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex.Nat Commun. 2025, 16:1282.(Independent Corresponding Author)

11. Zhuang J, Shang Q, Rastinejad F*,Wu D*. Decoding Allosteric Control in Hypoxia-Inducible Factors.J Mol Biol. 2024, 436: 168352.(*Co-corresponding authors)

10. Li P, Tian Y, Shang Q, Tang C, Hou Z, Li Y, Cao L, Xue S, Bian J, Luo C,Wu D*, Li Z*, Ding H*. Discovery of a highly potent NPAS3 heterodimer inhibitor by covalently modifying ARNT.Bioorg Chem. 2023, 139: 106676.(*Co-corresponding authors)

9. Song W, Zhuang J, Zhang N, Ren X, Xu W, Guo M, Diao X, Liu C, Jin J,Wu D*, Zhang Y*. SAR study of 1,2-benzisothiazole dioxide compounds that agonize HIF-2 stabilization and EPO production.Bioorg Med Chem. 2023, 77: 117041.(*Co-corresponding authors)

8. Sun X, Jing L, Li F, Zhang M, Diao X, Zhuang J, Rastinejad F,Wu D. Structures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers reveal new dimerization modalities in the bHLH-PAS transcription factor family.Proc Natl Acad Sci USA. 2022, 119: e2208804119. (Independent Corresponding Author)

7. Ren X, Diao X, Zhuang J*,Wu D*. Structural basis for the allosteric inhibition of hypoxia-inducible factor 2 by belzutifan.Mol Pharmacol. 2022, 102: 240-247.(*Co-corresponding authors)

6. Diao X, Ye F, Zhang M, Ren X, Tian X, Lu J, Sun X, Hou Z, Chen X, Li F, Zhuang J, Ding H, Peng C, Rastinejad F*, Luo C*,Wu D*. Identification of oleoylethanolamide as an endogenous ligand for HIF-3α.Nat Commun. 2022, 13: 2529.(*Co-corresponding authors)

5. Zhuang J, Liu Q,Wu D*, Tie L*. Current strategies and progress for targeting the "undruggable" transcription factors.Acta Pharmacol Sin. 2022, 43: 2474-2481.(*Co-corresponding authors)

4. Li F, Song C, Zhang Y,Wu D. Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs.Acta Biochim Biophys Sin (Shanghai). 2022, 54: 12-24.(Independent Corresponding Author)

3.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.(*Co-corresponding authors)[Recommended by F1000Prime]

2. 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.

1.Wu D, Potluri N, Lu J, Kim Y, Rastinejad F. Structural integration in hypoxia-inducible factors.Nature. 2015, 524: 303-308. [Recommended by F1000Prime] [Highlighted in the “News&Views” section ofNature]

Ⅱ.Field of Structural and Functional Studies and Targeted Molecular Discovery for Other Drug Target Proteins

5.Li F*, Zhang M, Liu C, Cheng J, Yang Y, Peng X, Li Z, Cai W, Yu H, Wu J, Guo Y, Geng H, Fa Y, Zhang Y,Wu D*, Yin Y*. De novo discovery of a molecular glue-like macrocyclic peptide that induces MCL1 homodimerization.Proc Natl Acad Sci USA. 2025, 122: e2426006122.(*Co-corresponding authors)

4.Liu J, Sun X, Zhuang J, Liu Z, Xu C,Wu D*, Wu C*. Biphenyl-dihydrothiazole-cyclized peptide libraries for peptide ligand and drug discovery.Sci. China Chem.2025, 68, 1434-1444.(*Co-corresponding authors)

3.Cui J, Liu X, Shang Q, Sun S, Chen S, Dong J, Zhu Y, Liu L, Xia Y, Wang Y, Xiang L, Fan B, Zhan J, Zhou Y, Chen P, Zhao R, Liu X, Xing N*,Wu D*, Shi B*, Zou Y*. Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance.Mol Cancer. 2024, 23: 86.(*Co-corresponding authors)

2.Li F*, Liu J, Liu C, Liu Z, Peng X, Huang Y, Chen X, Sun X, Wang S, Chen W, Xiong D, Diao X, Wang S, Zhuang J, Wu C*,Wu D*. Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy.Nat Commun.2024, 15: 1476.(*Co-corresponding authors)

1. 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. [Recommended by F1000Prime]

Ⅲ.Field of Structural Elucidation and Catalytic Mechanism Studies for Biosynthesis-Related Enzymes

4.Chen Y, Jing L, Peng M, Cai C, Shi J, Ge W, Liu Y, Shang Z, Ma J*,Wu D*, Ju J*. Enzymatic insights into the unusual formation of benzolactone and benzopyran in the biosynthesis of spiromarmycin.ACS Catal.2025, 15: 2809-2821.(*Co-corresponding authors)

3.Chen X, Zhao H, Wang C, Hamed M, Shang Q, Yang Y, Diao X, Sun X, Hu W, Jiang X, Zhang Y, Hirsch AKH,Wu D*, Zhuang J*. Two natural compounds as potential inhibitors against theHelicobacter pyloriandAcinetobacter baumanniiIspD enzymes.Int J Antimicrob Agents. 2024, 63: 107160.(*Co-corresponding authors)

2.Wang X, Chen X, Wang ZJ, Zhuang M, Zhong L, Fu C, Garcia R, Müller R, Zhang Y, Yan J*,Wu D*, Huo L*. Discovery and characterization of a myxobacterial lanthipeptide with unique biosynthetic features and anti-inflammatory activity.J Am Chem Soc.2023, 145: 16924-16937.(*Co-corresponding authors)

1. 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.(*Co-corresponding authors)[Selected as a "Spotlight Paper" in the Field of Organic Chemistry and Chemical Biology]

Honors and awards

1.2022 Distinguished Young Chang Jiang Scholar (Chair in Novel Drug Discovery)Ministry of Education, People's Republic of China.

2. 2019 Taishan Scholar of Shandong Province (Young Expert Program)

3. 2016 Qilu Young Scholar of Shandong University

Patents

1.ZL 2020 1 1422022.9: "Defining Domain Swap Module Controlling Altered Lipopeptide Sidechain Length, Its Mutant Derivatives, and Use Thereof". (Granted)

2.ZL 2020 1 1423361.9: "Defining Amino Acid Site Controlling Altered Lipopeptide Aliphatic Chain Length, Its Mutant Derivatives, and Use Thereof" .(Granted)

3.ZL 2021 1 0629888.5: "Synthetic Protocol for Benzoisothiazole and Benzothiophene Derivatives, and Pharmaceutical Utility Thereof" .(Granted)

4.ZL 2021 1 1242267.8: "Synthesis and Therapeutic Applications of HSP 90α Isoform-Specific Inhibitors". (Granted)