4HBM

Ordering of the N Terminus of Human MDM2 by Small Molecule Inhibitors

Summary for 4HBM

• Entry DOI: 10.2210/pdb4hbm/pdb
• Related: 4ERE 4ERF
• Descriptor: E3 ubiquitin-protein ligase Mdm2, {(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(2S)-1-hydroxybutan-2-yl]-2-oxopiperidin-3-yl}acetic acid (3 entities in total)
• Functional Keywords: mdm2, p53, protein protein interaction, inhibitor, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 8
• Total formula weight: 112367.06

Authors

Huang, X. (deposition date: 2012-09-28, release date: 2012-10-17, Last modification date: 2024-02-28)

Primary citation

Michelsen, K.,Jordan, J.B.,Lewis, J.,Long, A.M.,Yang, E.,Rew, Y.,Zhou, J.,Yakowec, P.,Schnier, P.D.,Huang, X.,Poppe, L.
Ordering of the N-terminus of human MDM2 by small molecule inhibitors.
J.Am.Chem.Soc., 134:17059-17067, 2012

PubMed Abstract: Restoration of p53 function through the disruption of the MDM2-p53 protein complex is a promising strategy for the treatment of various types of cancer. Here, we present kinetic, thermodynamic, and structural rationale for the remarkable potency of a new class of MDM2 inhibitors, the piperidinones. While these compounds bind to the same site as previously reported for small molecule inhibitors, such as the Nutlins, data presented here demonstrate that the piperidinones also engage the N-terminal region (residues 10-16) of human MDM2, in particular, Val14 and Thr16. This portion of MDM2 is unstructured in both the apo form of the protein and in MDM2 complexes with p53 or Nutlin, but adopts a novel β-strand structure when complexed with the piperidinones. The ordering of the N-terminus upon binding of the piperidinones extends the current model of MDM2-p53 interaction and provides a new route to rational design of superior inhibitors.

PubMed: 22991965
DOI: 10.1021/ja305839b

Experimental method

X-RAY DIFFRACTION (1.9 Å)