Zhihao Zhuang

Biography

​(b. 1976) B.S., 1997, Sichuan University; Ph.D., 2003, University of New Mexico; Postdoctoral Fellow, 2003-2007, Pennsylvania State University

Areas of Research

Protein posttranslational modification (PTM) by ubiquitin (Ub) and ubiquitin-like proteins; Probes, inhibitors and assay platforms against deubiquitinases (DUB); Ubiquitin ligase, protein degradation and PROTACs; Diagnostics and therapeutics in neurological disorders such as Parkinson’s disease and cancer.

Current Research

Our research program is at the interface of chemistry and biology. Our current efforts are directed toward understanding protein posttranslational modification (PTM) by ubiquitin (Ub) and ubiquitin-like proteins (ISG15 and SUMO) in cellular processes including protein degradation, DNA damage tolerance and mitophagy. We focus on the function, structure and catalysis of the proteins and complexes involved in ubiquitination/deubiquitination, deISGylation and protein homeostasis. We develop chemical approaches for protein ubiquitination, activity-based Ub probes and inhibitors against deubiquitinases (DUBs). We also develop new PROTAC (proteolysis-targeting chimera) strategies for targeted protein degradation for treating human diseases particularly neurological disorder and cancer. We address these research problems at a molecular level by employing a broad range of biochemical, synthetic, biophysical, and molecular and cell biology approaches.

Representative Publications

Gui W, Shen S, Zhuang Z, Photocaged Cell-Permeable Ubiquitin Probe for Temporal Profiling of Deubiquitinating Enzymes J. Am. Chem. Soc. (2020) doi: 10.1021/jacs.9b12426

Paudel P, Zhang Q, Leung C, Greenberg HC, Guo Y, Chern YH, Dong A, Li Y, Vedadi M, Zhuang Z, Tong Y. Crystal structure and activity-based labeling reveal the mechanisms for linkage-specific substrate recognition by deubiquitinase USP9X PNAS (2019), 116(15):7288.

Gui W, Ott CA, Yang K, Chung JS, Shen S, and Zhuang Z. Cell-Permeable Activity-Based Ubiquitin Probes Enable Intracellular Profiling of Human Deubiquitinases. J. Am. Chem. Soc. (2018), 140(39):12424.

Gong P, Davidson GA, Gui W, Yang K, Bozza WP, Zhuang Z. Activity-based ubiquitin-protein probes reveal target protein specificity of deubiquitinating enzymes. Chemical Science. (2018), 9(40):7859.

Ott C, Baljinnyam B, Zakharov A, Jadhav A, Simeonov A, Zhuang Z. Cell Lysate-Based AlphaLISA Deubiquitinase Assay Platform for Identification of Small Molecule Inhibitors. ACS Chem Biol. (2017), 12(9):2399.