Despite the latest impetus toward harnessing kinetically- and functionally-privileged cysteines for electrophilic-drug design, identifying these sensors remains challenging. We designed “G-REX”—a technique that allows controlled release of reactive electrophilic species (RES) in vivo. Mitigating toxicity/off-target effects associated with uncontrolled bolus RES exposure, G-REX tagged first-responding innate cysteines that bind RES under true kcat/Km conditions. When coupled with our recently-developed T-REX (Parvez et al. Nature Protocols 2016 and Long et al. Nature Chemical Biology 2017), this G-REX/T-REX double tap strategy (Zhao et al. ACS Central Science 2018) addresses unmet needs in understanding the functional biology of RES signaling and target ID: G-REX enables direct target-ID of privileged sensor-cysteines (capable of competitively sensing a specific RES and eliciting dominant signaling output as a consequence of ‘on-target’ RES modifications at low occupancy); while T-REX enables surgical interrogations into precision ‘target engagement’ of these newly-identified privileged cysteines. Together, our coupled platform offers a new ability to discover and functionally decipher novel protein-cysteine signaling codes on a scale and resolution (space, time, and target cysteine precision) hitherto inaccessible.

Beyond proteomics: Simultaneous profiling and decoding precision protein-cysteine signaling axes in living cells, fish, and worms

256th National Meeting (2018)

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