Structure of free MDM2 N-terminal domain reveals conformational adjustments that accompany p53-binding

Critical to the inhibitory action of the oncogene product, MDM2, on the tumour suppressor, p53, is association of the N-terminal domain of MDM2 (MDM2(N)) with the transactivation domain of p53. The structure of MDM2(N) was previously solved with a p53-derived peptide, or small-molecule ligands, occupying its binding cleft, but no structure of the nonliganded MDM2(N) (i.e. the apo-form) has been reported. Here, we describe the solution structure and dynamics of apo-MDM2(N) and thus reveal the nature of the conformational changes in MDM2(N) that accompany binding of p53. The new structure suggests that p53 effects displacement of an N-terminal segment of apo-MDM2(N) that occludes access to the shallow end of the p53-binding cleft. MDM2(N) must also undergo an expansion upon binding, achieved through a rearrangement of its two pseudosymetrically related sub-domains resulting in outward displacements of the secondary structural elements that comprise the walls and floor of the p53-binding cleft. MDM2(N) becomes more rigid and stable upon binding p53. Conformational plasticity of the binding cleft of apo-MDM2(N) could allow the parent protein to bind specifically to several different partners, although, to date, all the known liganded structures of MDM2(N) are highly similar to one another. The results indicate that the more open conformation of the binding cleft of MDM2(N) observed in structures of complexes with small molecules and peptides is a more suitable one for ligand discovery and optimisation. (c) 2005 Elsevier Ltd. All rights reserved.