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

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

doi:10.1016/j.febslet.2010.05.058

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Volume 584, Issue 14 , Pages 3035-3041, 16 July 2010

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

Edited by Christian Griesinger

Maria C. Sanchez
- University of Edinburgh, Joseph Black Chemistry Building, West Mains Road, Edinburgh EH9 3JJ, United Kingdom
Jonathan G. Renshaw
- AstraZeneca Pharmaceuticals, Cell, Protein and Structural Sciences, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom
Gareth Davies
- AstraZeneca Pharmaceuticals, Cell, Protein and Structural Sciences, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom
Paul N. Barlow
- University of Edinburgh, Joseph Black Chemistry Building, West Mains Road, Edinburgh EH9 3JJ, United Kingdom
- Corresponding author. Fax: +44 1316507055.
Martin Vogtherr
- AstraZeneca Pharmaceuticals, Cell, Protein and Structural Sciences, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom
- Correspondence to: M. Vogtherr, Merck KGaA, Frankfurter Str. 250, D-64293 Darmstadt, Germany. Fax: +49 6151 72913535.

Received 28 April 2010; received in revised form 25 May 2010; accepted 26 May 2010. published online 31 May 2010.

Abstract

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.