(A) MRG15 binding releases the autoinhibitory loop of ASH1L. The autoinhibitory loop (in magenta) is ordered and blocks the histone tail-binding channel when ASH1L is not bound to MRG15 (left, PDB: 3OPE [78]). In the presence of MRG15, the autoinhibitory loop of ASH1L becomes disordered (right, PDB: 6AGO [88]). (B) Molecular mechanism for the displacement of the autoinhibitory loop in ASH1L. The superposition of ASH1L-MRG15 structure (structure in cyan, Left: 6AGO [88]; right: 6INE [89]) with ASH1L alone (grey, PDB: 3OPE [78]) indicates the binding of MRG15 induces a series of subtle conformational changes to destabilise the autoinhibitory loop. The autoinhibitory loop is ordered in the structure of ASH1L alone and is shown in magenta. The key residues involved in the displacement of the autoinhibitory loop are shown in sticks. In the left panel, Lee et al. [88] suggested that the hydrophobic network between MRG15 and ASH1L results in the reorientation of H2193 and Y2207, leading to the disorder of the autoinhibitory loop. In the right panel, Hou et al. [89] proposed that binding of MRG15 stabilises the conformations of P2067 and P2064, leading to the conformational changes of W2152, and further triggers a cascade of subtle rearrangements of the residues surrounding the SAM binding pocket. This results in a small shift of SAM and eventually leads to the disorder of the autoinhibitory loop.