Acetyl-lysine binding pocket

Figure 20.2 Architecture of the acetyl-lysine binding pocket, (a) Ribbon diagram of the first bromodomain of BRD4 [BRD4(1),...

Of particular interest is the way in which the side chains that line the acetyl lysine binding pocket and neighbouring regions dictate the selectivity of... 

Molecule A is an analogue of N-acetyl-lysine that is likely to inhibit trypsin. The positively charged e-ammonium group will bind in trypsin s substrate specificity pocket. Additionally, the B-O group is likely to bind in the oxyanion hole (Figure 9.9). Because there is no peptide bond to be cleaved, the inhibitor will remain bound to the enzyme and will interfere competitively with the binding of natural substrates. 

The X-ray structures of several human HDACs have been solved and reveal a catalytic mechanism akin to other metalloenzymes that carry out amide hydrolysis (Figure 4.3). The acetyl-lysine substrate is positioned within a narrow channel that ends with a catalytic zinc cation. The metal serves to activate a water molecule to make it more nucleophilic and simultaneously coordinates to the acetyl group to make it a better electrophile. The attack of water results in a tetrahedral intermediate that collapses to give lysine and acetate, the latter leaving through an exit channel separate from the substrate binding pocket... 

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