The team of Professor Mao Youdong from the School of Physics has made a breakthrough in the reconstruction of protein dynamics regulation by artificial intelligence-assisted time-resolved cryo-EM

The team of Professor Mao Youdong, Institute of Condensed Matter Physics and Materials Physics, School of Physics, Peking University, State Key Laboratory of Artificial Microstructure and Mesoscopic Physics, National Center for Biomedical Imaging Science, Peking University-Tsinghua Life Science Joint Center, and Center for Quantitative Biology The self-developed deep learning high-precision four-dimensional reconstruction technology, and the development and application of time-resolved cryo-electron microscopy have clarified the kinetic regulation and conformational reprogramming mechanism of the human proteasome at the atomic level

At the same time, the researchers, reviewers and the Nature editorial team jointly published a presentation titled "Control of human protein-degradation machinery revealed" in the Research Briefing column.

Regulation of protein degradation is an extremely important fundamental biochemical process that plays a key role in major cellular and molecular processes such as cell cycle, signal transduction, immune response, gene regulation, metabolism, neurodegeneration, cancer tumors, viral infection, and protein toxicity responses.

Molecular machines of life achieve their special functions through highly complex non-equilibrium kinetic processes and structural changes, which are then precisely regulated by various complex intermolecular interactions

Professor Mao Youdong's team has long been committed to the development of kinetic reconstruction methods based on cryo-electron microscopy, focusing on the structure, function, kinetic mechanism and targeted regulatory molecule design of target systems with great clinical application prospects such as proteasome and inflammasome.

(A) One of the atomic structural models of the degradation of polyubiquitinated substrates by the proteasome complex under the regulation of USP14; (B) Time-resolution cryo-electron microscopy analysis of the temporal evolution of the statistical distribution of 13 intermediate states with the process of protein degradation (Youdong Mao , CC BY 4.

The process of scientific research is always difficult and tortuous.

The next extreme challenge is "three-dimensional classification.

The study found that the activation of USP14 is dependent on both ubiquitin recognition and the binding of the proteasome RPT1 subunit

Parallel pathway model of USP14-regulated proteasomal substrate degradation obtained by time-resolved cryo-EM analysis (Youdong Mao, CC BY 4.

Zhang Shuwen, a postdoctoral fellow of Peking University's "Boya", and Zou Shitao, a 2019 doctoral student at the School of Physics, Peking University, are the co-first authors of the paper, and Mao Youdong is the corresponding author

The above research work was supported by the Beijing Natural Science Foundation, the National Natural Science Foundation of China, the National Science Foundation for Distinguished Young Scholars, and the Peking University-Tsinghua Life Science Joint Center