FIGURE 1.

Overall crystal structure of human HdmX in complex with the peptide-analogue Ac-Phe-Met-Aib-Pmp-Trp-Glu-Ac₃c-Leu-NH₂ (compound 1). A, van der Waals surface representation showing the complex between HdmX (carbons in yellow, nitrogens in blue, oxygens in red, and sulfurs in brown) and the p53 peptide analogue compound 1 (ball-and-stick-model, carbons in cyan). Selected water molecules and hydrogen bonds are shown in white. The pockets into which Phe¹⁹, Trp²³, and Leu²⁶ of p53 bind are indicated. Compound 1 makes several water-mediated interactions with HdmX and two direct hydrogen bonds (with CO-Met⁵³ and OE1-Gln⁷¹). The phosphonate of the Pmp residue does not make direct interactions with HdmX. The most important differences with Hdm2 are seen for the Leu pocket and the bottom of the Trp pocket (Fig. 3), whereas the Phe pockets are similar. B, chemical structures of compound 1 (Ac-Phe-Met-Aib-Pmp-Trp-Glu-Ac₃c-Leu-NH₂) and the derivative compound 2, which has a 6-chlorine substituent on the indole ring. The orientation of the chemical structure drawing is adapted to resemble A and C, i.e. with the C terminus on the left and the N terminus on the right. C, compound 1 fitted into the 2F_o-F_c electron density map. Figs. 1, A and C, 2, and 3 were generated with PyMOL (39).