Overlay of residues comprising the Trp pocket in M011-Mdm2 and Cpd2-Mdm4 structures.

M011 peptide (green) 6-chloro group of W23 projects deeper into the Mdm4 (cyan) Trp pocket compared to linear Cpd2 peptide (magenta), potentially clashing with the L98 side chain. The position of the corresponding I99 residue in Mdm2 (blue) results in a wider Trp pocket. The mutation of F86 in Mdm2 to L85 in Mdm4 results in the loss of a favorable Van der Waals interaction with the 6-chloro moiety of W23. In addition, the absence of F86 results in a conformational change in the α2 helix between the two proteins. This causes a reorientation of the L98 residue in Mdm4 in comparison to I99 of Mdm2 and brings it into closer proximity to the 6-chloro moiety, forming a less energetically favorable hydrophobic interaction. Several regions of Mdm2/Mdm4 have been omitted for clarity.