Proteomics

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Light-activatable, 2,5-disubstituted tetrazoles for the proteome-wide profiling of aspartates and glutamates in living bacteria


ABSTRACT: Covalent inhibitors have recently seen a resurgence of interest in drug development. Nevertheless, compounds, that do not rely on an enzymatic activity, have almost exclusively been developed to target cysteines. Expanding the scope to other amino acids would be largely facilitated by the ability to globally monitor their engagement by covalent inhibitors. Here, we present the use of light-activatable 2,5-disubstituted tetrazoles that allow quantifying close to 9000 aspartates and glutamates in the bacterial proteome with excellent selectivity. Using these probes, we competitively map the binding sites of two isoxazolium salts and introduce hydrazonyl chlorides as a new class of carboxylic acid-directed covalent protein ligands. As the probes are unreactive prior to activation, they allow global profiling even in living Gram-positive and Gram-negative bacteria. Taken together, this method to monitor aspartates and glutamates proteome-wide will lay the foundation to efficiently develop covalent inhibitors targeting these amino acids.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Escherichia Coli Staphylococcus Aureus

SUBMITTER: Stephan M. Hacker  

LAB HEAD: Stephan M. Hacker

PROVIDER: PXD016659 | Pride | 2020-04-14

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
190125_KAB_190124_1_1.raw Raw
190125_KAB_190124_1_2.raw Raw
190125_KAB_190124_2_1.raw Raw
190125_KAB_190124_2_2.raw Raw
190125_KAB_190124_3_1.raw Raw
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Publications

Light-Activatable, 2,5-Disubstituted Tetrazoles for the Proteome-wide Profiling of Aspartates and Glutamates in Living Bacteria.

Bach Kathrin K   Beerkens Bert L H BLH   Zanon Patrick R A PRA   Hacker Stephan M SM  

ACS central science 20200413 4


Covalent inhibitors have recently seen a resurgence of interest in drug development. Nevertheless, compounds, which do not rely on an enzymatic activity, have almost exclusively been developed to target cysteines. Expanding the scope to other amino acids would be largely facilitated by the ability to globally monitor their engagement by covalent inhibitors. Here, we present the use of light-activatable 2,5-disubstituted tetrazoles that allow quantifying 8971 aspartates and glutamates in the bact  ...[more]

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