Disulfide trapping cysteine residues

Researchers at Sunesis pharmaceuticals have developed a fragment-based drug discovery method termed tethering [25]. The approach, which is illustrated in Scheme 2.6, shares a number of features with DCC. Whereas protein-directed DCLs equilibrate small molecules via disulfide formation, say, in the presence of a protein that acts as a thermodynamic trap, tethering uses a cysteine residue on the protein surface to reversibly capture small-molecule thiol fragments from solution. Tethering is designed... 

Fig. 17.7. Engineered protein designed for mechanochemistry studies, (a) A pair of cysteine residues introduced into the 127 protein (positions 32 and 75 suifur atoms as spheres) spontaneously form a buried disuifide bond. (b). In response to an unfolding force, the protein extends right up to the disuifide bond. Unfoiding exposes the disulfide bond to the solution, (c) Then, a nucieophiie such as DTT can initiate a Sn2 reaction, leading to the reduction of the disuifide bond and the concomitant extension of the amino acids that were trapped behind the disuifide bond. This sequence of events nnambiguousiy identifies individual disulfide bond reduction events, allowing for the stndy of a pulling force on a Sn2 chemicai reaction...

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