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I. 转录因子靶标蛋白的结构功能研究和靶向分子发现领域

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转录因子蛋白bHLH-PAS(basic helix-loop-helix-PER-ARNT-SIM)家族是一类可作为潜在药物靶标的转录因子家族。转录因子的功能失调常与重大疾病密切相关(特别是肿瘤等)而且种类繁多(>1000 种),但却通常被认为“难以靶向”(undruggable)。主要原因是转录因子大多缺乏明确的配体结合位点,目前常用的细胞水平化合物筛选体系靶向性较差,以及活性调控机制不清楚等。为了应对这三方面的挑战,本课题组围绕疾病相关的转录因子,首先通过蛋白结构解析直观呈现配体结合位点,基于配体与蛋白的直接相互作用筛选靶向小分子,并以共晶和质谱等多种手段揭示其作用机制,搭建起一套独特而有效的转录因子新靶标和新靶向分子发现平台。


代表论文

16. Zhuang J, Shang Q, Rastinejad F*,Wu D*. Decoding allosteric control in hypoxia-inducible factors.J Mol Biol.2024, 436: 168352.(*共同通讯作者)

15. 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.(*共同通讯作者)

14. 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.(*共同通讯作者)

13. 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.(独立通讯作者)

12. 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.(*共同通讯作者)

11. 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.(*共同通讯作者)

10. 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.(*共同通讯作者)

9. 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.(独立通讯作者)[封面文章]

8. 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]

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

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

5. 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.

4. 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.

3. 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]

2. 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]

1. 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]