Structural Adaptation of Secondary p53 Binding Sites on MDM2 and MDMX.

ABSTRACT: The thermodynamics of secondary p53 binding sites on MDM2 and MDMX were evaluated using p53 peptides containing residues 16-29, 17-35, and 1-73. All the peptides had large, negative heat capacity (ΔC_p), consistent with the burial of p53 residues F19, W23, and L26 in the primary binding sites of MDM2 and MDMX. MDMX has a higher affinity and more negative ΔC_p than MDM2 for p53_17-35, which is due to MDMX stabilization and not additional interactions with the secondary binding site. ΔC_p measurements show binding to the secondary site is inhibited by the disordered tails of MDM2 for WT p53 but not a more helical mutant where proline 27 is changed to alanine. This result is supported by all-atom molecular dynamics simulations showing that p53 residues

SUBMITTER: Higbee PS 

PROVIDER: S-EPMC12624572 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature