Ekaterina Vinogradova, Daniel Lazar, Radu Suciu, Yujia Wang, Giulia Bianco, Yu Yamashita, Vincent Crowley, Dave Remillard, Kenneth Lum, Gabriel Simon, Esther Kemper, Michael Lazear, Sifei Yin, Megan Blewett, Melissa Dix, Nhan Nguyen, Maxim Shokhirev, Emily Chin, Luke Lairson, Stefano Forli, John Teijaro, Benjamin Cravatt
BioRxiv, 2019
doi: https://www.biorxiv.org/content/10.1101/808113v1
Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving direct functional perturbation and/or ligand-induced degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells, underscoring the potential of electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs.
Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition
Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...
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Katharine Gilbert, Aini Vuorinen, Arron Aatkar Peter Pogány, Jonathan Pettinger, Joanna M. Kirkpatrick, Katrin Rittinger∥, David House, Glen...
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Yejin Jung, Naotaka Noda, Junichiro Takaya, Masahiro Abo, Kohei Toh, Ken Tajiri, Changyi Cui, Lu Zhou, Shin-ichi Sato, and Motonari Uesugi A...
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Madeline E Kavanagh, Benjamin D Horning, Roli Khattri, Nilotpal Roy, Justine P Lu, Landon R Whitby, Jaclyn C Brannon, Albert Parker, Joel M ...