The even bigger surprise was

The even bigger surprise was the second feature of both structures. Interestingly, binding of the MRG domain hardly altered the conformation of the SET domain compared with its apo state (An et al., 2011). What did change, however, is the conformation of the ASH1L auto-inhibitory loop (Figure 1). Despite binding of the MRG domain distant from the AI loop and lack of direct contacts with it, the AI loop becomes disordered in the presence of the MRG domain. Consequently, the blockage of the substrate-binding site is released and the active site adopts a catalytically competent configuration, allowing substrate binding. Hou et al. (2019) suggest that pd0325901 a cascade of subtle rearrangements of residues surrounding the S-adenosyl-methionine (SAM) binding pocket lead to a small shift of the SAM molecule and finally results in the destabilization of the AI loop. In comparison, Lee et al. (2019) put stronger emphasis on the involvement of two key residues in the vicinity (H2193 and Y2207) that undergo conformational rearrangements, subsequently resulting in loop displacement and ASH1L activation. Despite these subtle differences, both groups suggest that MRG15 recruitment leads to changes in SAM binding. Thus, SAM apparently serves as a mediator that transduces MRG15-induced conformational perturbation from one side of the SAM binding pocket to the AI loop on the opposite side. Taken together, the studies of Lee et al. (2019) and Hou et al. (2019) represent a fascinating example for the fine-tuning of an enzymatic activity by subtle conformational changes that are triggered by the collaborative action of an allosteric regulator and an enzyme’s co-factor molecule. The results now provide a solid basis for future research on ASH1L and contribute to the current knowledge of dynamic chromatin regulation by histone modifying enzymes.
Acknowledgments