Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs

ABSTRACT: A 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.

INSTRUMENT(S): LTQ Orbitrap Velos, Orbitrap Fusion, LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Peripheral Blood Mononuclear Cell, Permanent Cell Line Cell, Cell Culture, Blood

SUBMITTER: Yujia Wang  

LAB HEAD: Benjamin F. Cravatt

PROVIDER: PXD015104 | Pride | 2019-10-29

REPOSITORIES: Pride