研究方向

本研究组主要通过发展新型交叉物理生物学方法，研究泛素蛋白酶体系统（Ubiquitin-Proteasome System，UPS）及其对细胞关键生命分子过程调控的基本规律。当前主要研究方向包括：（1）聚焦冷冻电镜显微学和人工智能的交叉研究，发展新型高分辨动力学重建方法，研究UPS蛋白质降解动态调控机制，研究UPS调控人类细胞中炎症、癌症、神经退行、病毒感染以及糖脂代谢等关键分子过程的结构、动力学和功能关系；（2）研究新型机器学习和动力学辅助药物发现和反向疫苗免疫原设计方法，发展超高分辨冷冻电镜方法，研发靶向UPS的新型化合物；（3）以调控UPS核心组分（26S、泛素受体、去泛素化酶、E3泛素化酶等）为主要干预手段，研发新型靶向分子胶技术和多特异性靶向降解疗法，为攻克神经退行疾病、癌症肿瘤和心脑血管疾病等提供临床候选原创新药分子。

代表性学术论文

1. Dong Y, Zhang S, Wu Z, Li X, Wang W, Zhu Y, Stoilova-McPhie S, Lu Y, Finley D, Mao Y*.Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome. Nature 2019; 565: 49-55.

2. Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q, Hauenstein AV, Wu Z, Nunez G, Mao Y*, Wu H*. Structural mechanism for NEK7-mediated NLRP3 inflammasome activation. Nature 2019; 570:338-343.

3. Wang WL, Yu Z, Castillo-Menendez LR, Sodroski J, Mao Y*. Robustness of signal detection in cryo-electron microscopy via a bi-objective-function approach. BMC Bioinformatics 2019; 20:169.

4. Zhu Y, Wang WL, Yu D, Ouyang Q, Lu Y*, Mao Y*. Structural mechanism for nucleotide-driven remodeling of the AAA-ATPase unfoldase in the activated human 26S proteasome. Nat. Commun. 2018; 9: 1360.

5. Dong Y, Chen S, Zhang S, Sodroski J, Yang Z, Liu D, Mao Y*. Folding DNA into a lipid-conjugated nanobarrel for controlled reconstitution of membrane proteins. Angew. Chem. Int. Ed. 2018; 57: 2072-2076.

6. Lu Y, Wu J, Dong Y, Chen S, Sun S, Ma YB, Ouyang Q, Finley D, Kirschner MW*, Mao Y*. Conformational landscape of the p28-bound human proteasome regulatory particle. Mol. Cell 2017; 67: 322-333.e6.

7. Wu J, Ma Y, Congdon C, Brett B, Chen S, Ouyang Q, Mao Y*. Massively parallel unsupervised single-particle cryo-EM data clustering via statistical manifold learning. PLoS One 2017; 12: e0182130.

8. Zhu Y, Ouyang Q, Mao Y*. A deep convolutional neural network approach to single-particle recognition in cryo-electron microscopy. BMC Bioinformatics 2017; 18: 348.

9. Chen S, Wu J, Lu Y, Ma YB, Lee BH, Yu Z, Ouyang Q, Finley D, Kirschner MW*, Mao Y*. Structural basis for dynamic regulation of the human 26S proteasome. Proc. Natl. Acad. Sci. USA 2016; 113: 12991-12996.

10. Zhang L, Chen S, Ruan J, Wu J, Tong AB, Yin Q, Li Y, David L, Lu A, Wang WL, Marks C, Ouyang Q, Zhang X, Mao Y*, Wu H*. Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization. Science 2015; 350: 404-409.