Youdong Mao, Ph.D.

 

E-mail：ymao_at_pku.edu.cn

Phone：+86-10-62750295

 

Research Summary： 

The Mao Laboratory focuses on the mechanistic investigation of ubiquitin-proteasome system (UPS) and its regulation of essential intracellular processes by leveraging multidisciplinary approaches in physical biology. The major research topics currently being conducted in the laboratory are of three folds:

(1) We are developing novel AI-based classification algorithms for high-resolution 4D cryo-EM to reconstitute non-equilibrium dynamics of complex assembly. These novel approaches are applied to study how the proteasome is regulated at multiple levels by cellular proteins and how the UPS regulates important physiological processes involved in inflammation, carcinogenesis, neurodegeneration, viral infection, and metabolism.

(2) We are developing novel machine learning approaches for dynamics-based drug discovery and vaccine immunogen design. These methods are used to design new compounds targeting the UPS based on structural dynamics information obtained from high-resolution cryo-EM analysis.

(3) By targeting key components of the UPS, we are innovating multidisciplinary methods for designing molecular glue and for degradation-based therapeutics in combating cancer, neurodegenerative and cardiovascular diseases.

 

Selected Publications：

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.