MDM4 binds ligands via a mechanism in which disordered regions become structured

Maria C. Sanchez, Jonathan G. Renshaw, Gareth Davies, Paul N. Barlow, Martin Vogtherr

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

MDM2 and MDM4 are proteins involved in regulating the tumour suppressor p53. MDM2/4 and p53 interact through their N-terminal domains and disrupting this interaction is a potential anticancer strategy. The MDM2-p53 interaction is structurally and biophysically well characterised, whereas equivalent studies on MDM4 are hampered by aggregation of the protein. Here we present the NMR characterization of MDM4 (14-111) both free and in complexes with peptide and small-molecule ligands. MDM4 is more dynamic in its apo state than is MDM2, with parts of the protein being unstructured. These regions become structured upon binding of a ligand. MDM4 appears to bind its ligand through conformational selection and/or an induced fit mechanism; this might influence rational design of MDM4 inhibitors.

Original languageUndefined/Unknown
Pages (from-to)3035-3041
Number of pages7
JournalFEBS Letters
Issue number14
Publication statusPublished - 2010

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