Monday, February 28, 2022

Global profiling of phosphorylation-dependent changes in cysteine reactivity [@estherkemper1

Kemper, E.K., Zhang, Y., Dix, M.M. & Benjamin F. Cravatt.

Nat Methods, 2022

Proteomics has revealed that the ~20,000 human genes engender a far greater number of proteins, or proteoforms, that are diversified in large part by post-translational modifications (PTMs). How such PTMs affect protein structure and function is an  active  area  of  research  but  remains  technically  challenging  to  assess  on  a  proteome-wide  scale.  Here,  we  describe  a  chemical proteomic method to quantitatively relate serine/threonine phosphorylation to changes in the reactivity of cysteine residues, a parameter that can affect the potential for cysteines to be post-translationally modified or engaged by covalent drugs. Leveraging the extensive high-stoichiometry phosphorylation occurring in mitotic cells, we discover numerous cysteines that exhibit phosphorylation-dependent changes in reactivity on diverse proteins enriched in cell cycle regulatory pathways. The discovery  of  bidirectional  changes  in  cysteine  reactivity often  occurring  in  proximity  to  serine/threonine  phosphorylation events points to the broad impact of phosphorylation on the chemical reactivity of proteins and the future potential to create small-molecule probes that differentially target proteoforms with PTMs.

Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1

Adrian Hall, Jan Abendroth, Madison J. Bolejack, Tom Ceska, Sylvie Dell’Aiera, Victoria Ellis, David Fox, Cyril François, Muigai M. Muruthi,...