Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs
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Dix, Melissa M.
Remsberg, Jarrett R.
Gygi, Steven P.
Lawrence, R. Michael
Parker, Christopher G.
Cravatt, Benjamin F.
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CitationWang, Yujia, Melissa M. Dix, Giulia Bianco, Jarrett R. Remsberg, Hsin-Yu Lee, Marian Kalocsay, Steven P. Gygi, Stefano Forli, Gregory Vite, R Michael Lawrence, Christopher G. Parker, and Benjamin F .Cravatt. 2019. Expedited Mapping of the Ligandable Proteome Using Fully Functionalized Enantiomeric Probe Pairs. Nature Chemistry 11, no. 12: 1113-123.
AbstractA fundamental challenge in chemical biology and medicine is to understand and expand the fraction of the human proteome that can be targeted by small molecules. We recently described a strategy that integrates fragment-based ligand discovery with chemical proteomics to furnish global portraits of reversible small molecule-protein interactions in human cells. Excavating clear structure-activity relationships from these “ligandability” maps, however, was confounded by the distinct physicochemical properties and corresponding overall protein-binding potential of individual fragments. Here, we describe a compelling solution to this problem by introducing a next-generation set of fully functionalized fragments (FFFs) differing only in absolute stereochemistry. Using these enantiomeric probe pairs, or “enantioprobes”, we identify numerous stereoselective protein-fragment interactions in cells and show that these interactions occur at functional sites on proteins from diverse classes. Our findings thus indicate that incorporating chirality into FFF libraries provides a robust and streamlined method to discover ligandable proteins in cells.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37373016
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