Crystallographic unique interaction sites of the M011 stapled peptide bound to the N-terminal p53 binding domain of Mdm2-M62A (6–125).

A, The 2Fo-Fc electron density map, contoured at 1.5 σ, clearly denotes the amino acid residues involved in recognizing the conserved Mdm2 binding motif (F19, 6-Cl-W23 and L26, shown in bold). Green mesh highlights residues from Mdm2 and blue mesh indicates residues from the stapled M011 peptide. The residues involved in recognizing the M011 peptide in the other complex show negligible conformational differences. B, Overlay of the two unique complexes. The M011 peptide is highlighted in yellow with the staple colored orange (chain D) and green with the staple coloured charcoal (chain C), whilst Mdm2 (chain A) is shown in blue and Mdm2 (Chain B) is highlighted in magenta. For clarity only side chains of the interacting peptide residues (F19, 6-Cl-W23, L26) are depicted. C, Small conformational differences are observed in the hinge region of Mdm2 peptide binding pocket. Fluctuations in the lid/hinge region (residues 18–26) in conjunction with Y100 and Y104 induce a conformation change of the M011 L26 residue projecting into the Leu pocket of Mdm2. Colouring scheme as in B.