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Abstract
<p class="first" id="P8">We previously reported interaction determination using unpurified
proteins (IDUP),
a method to selectively amplify DNA sequences encoding ligand:target pairs from a
mixture of DNA-linked small molecules and unpurified protein targets in cell lysates.
In this study, we applied IDUP to libraries of DNA-encoded bioactive compounds and
DNA-tagged human kinases to identify ligand:protein binding partners out of 32 096
possible combinations in a single solution-phase library × library experiment. The
results recapitulated known small molecule:protein interactions and also revealed
that ethacrynic acid is a novel ligand and inhibitor of MAP2K6 kinase. Ethacrynic
acid inhibits MAP2K6 in part through alkylation of a nonconserved cysteine residue.
This work validates the ability of IDUP to discover ligands for proteins of biomedical
relevance.
</p>
[1
]The Broad Institute of Harvard
and MIT, Howard Hughes Medical Institute, and the Department
of Chemistry
and Chemical Biology, Harvard University, 75 Ames Street, Cambridge,
Massachusetts 02142, United States