Figure 9
Comparison of the ERK5 allosteric ligand-binding mode with allosteric inhibitors of (a, b) MEK1/2 (PDB entries 1s9i and 1s9j; Ohren et al., 2004 ), (c) ITK (PDB entry 4m0y; Han et al., 2014 ) and (d) CDK2 (PDB entry 3py1; Betzi et al., 2011 ) highlights the changes in αC helix orientation and P-loop conformation associated with inhibitor binding. In (a), (c) and (d) the structures are oriented such that the viewer looks onto the kinase C-lobe, and the N-terminal β-sheet has been omitted for clarity. In (b) the view has been rotated 90° with respect to (a) to show the differences in P-loop conformation. Structures were superposed by matching residues corresponding to the β-sheet and hinge region of the N-terminal lobe of ERK5 kinase (amino acids 55–61, 70–88, 108–123 and 131–140). ERK5 (coloured as in Fig. 2 ), MEK (gold), ITK (cyan) and CDK2 (lilac) are shown in ribbon representation. Bound ligands are rendered as sticks with C atoms coloured green (compound 4), pink (ATP), cyan (MEK inhibitor; compound 7), magenta (ITK inhibitor; compound 8), purple (SU9516) and cyan (ANS; compound 9). |