Thursday, October 17, 2019

An activity-guided map of electrophile-cysteine interactions in primary human immune cells

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

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.

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...