Target Characterization

Discovery of reactive modifications harbored by disease-relevant proteins


This project is to discover the reactive modifications in such functionally uncharacterized and disease-relevant proteins (e.g., KEAP1 in cancer; amyloid precursor proteins in Alzheimer’s disease). Identification of their reactive groups has the potential to illuminate structural features that confer or impact function, to identify novel catalytic machinery, and to suggest new therapeutic strategies. Once the reactive groups are uncovered, covalent targeting by the probes offers a potential strategy for therapeutic intervention, as these probes can serve not only as discovery tools but also as potent inhibitors.

Selected Publications

Lin Z, Wang X, Bustin KA, He L, Suciu RM, Schek N, Ahmadi M, Hu K, Olsen EJ, Parsons WH, Witze ES, Morton PD, Gregus AM, Buczynski MW, Matthews ML. Hydrazines as versatile chemical biology probes and drug-discovery tools for cofactor-dependent enzymes bioRxiv (2020) [PDF] EJ Blaesi, GP Palowitch, K Hu, AJ Kim, HR Rose, RB Alapati, MG Lougee, HJ Kim, KO Tan, AT Taguchi, TN Laremore, RG Griffin*, C Krebs*, ML Matthews*, A Silakov*, JM Bollinger, Jr.*, BD Allen*, AK Boal* (*co-corresponding authors). Metal-free class Ie ribonucleotide reductase from pathogens initiates catalysis with a tyrosine-derived dihydroxyphenylalanine radical PNAS 115 (40), 10022-10027 (2018) [PDF] Matthews ML*, He L, Olson EJ, Horning BD, Correia BE, Yates JR, III, Dawson PE & Cravatt BF*. Chemoproteomic profiling and discovery of protein electrophiles in human cells Nat. Chem.  9, 234–243 (2017) [PDF]