Education
Date |
Affiliation |
Major |
Degree |
1999.9-2003.7 |
School of Life Sciences, Shandong University |
Biotechnology |
Bachelor |
2003.9-2008.7 |
Shanghai Institute of Materia Medica, CAS |
Drug Design |
PhD |
Research Experience
Date |
Affiliation |
Position |
2008.8-2011.7 |
University of California, Davis, USA |
Postdoctoral Fellow |
2011.8-2016.8 |
Sanford Burnham Prebys Medical Discovery Institute at Lake Nona, USA |
Postdoctoral Associate |
2016.9-Now |
Microbial Technology Institute / School of Life Sciences, Shandong University |
Professor |
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 oneα subunit and ARNT (also called HIF-β).We solved the complex structures of HIF-α and 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-2α protein.
Representative Publications
1. 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. 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]
3. 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.
4. Wu D, Rastinejad F. Structural characterization of mammalian bHLH-PAS transcription factors.Curr Opin Struct Biol. 2017, 43: 1-9.
5. 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. (#Co-first authors)
6. 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. [Spotlighted as one of three “articles of significant interest”]
7. 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. (#Co-first authors) [Commented by the editorial]
8. 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.
9. 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.
Honors and awards
2019 Taishan Scholar of Shandong Province (Young Expert Program)
2016 Qilu Young Scholar of Shandong University
