Mdm2-M62A (6–125) shows a high degree of conformational plasticity in the α2’ and ‘hinge’ helices capping the p53-binding pocket.

A,B The binding pockets that form when Mdm2 interacts with SAH-8 (A) and p53 WT peptide (B) are much more open when compared to the binding pockets formed in the two complexes of Mdm2:M06 found in the asymmetric unit. The key residue that is involved in forming the bottom of the binding pocket in the Mdm2 complexes with SAH-8 (A) and p53 WT (B) is Y100 (shown in red) on the α2’ helix, where it either closes the binding site by orientating itself inward or out towards the solvent, respectively. C, D In contrast, the binding pockets formed in the two crystallographically unique M06 complexes are capped by the ‘hinge’ helix of the lid (residues 20–24, highlighted in yellow). The helix is stabilized in this conformation by a hydrogen bond between Q24 (magenta) and the amide cap at the C-terminal of M06.