MDM4 binds ligands via a mechanism in which disordered regions become structured.
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.
University of Edinburgh, Edinburgh, United Kingdom.
Maria C
MC
Sanchez
Jonathan G
JG
Renshaw
Gareth
G
Davies
Paul N
PN
Barlow
Martin
M
Vogtherr
D006801:Humans; D008024:Ligands; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D008024:Ligands; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2