4J74

The 1.2A crystal structure of humanized Xenopus MDM2 with RO0503918 - a nutlin fragment

Summary for 4J74

• Entry DOI: 10.2210/pdb4j74/pdb
• Related: 1RV1 4IPF 4J3E 4J7D 4J7E
• Descriptor: E3 ubiquitin-protein ligase Mdm2, (4S,5R)-4,5-bis(4-chlorophenyl)-2-methyl-4,5-dihydro-1H-imidazole, SULFATE ION, ... (4 entities in total)
• Functional Keywords: mdm2, imidazoline, ligase-antagonist complex, e3 ubiquitin ligase, p53, nucleus, ligase/antagonist
• Biological source: Xenopus laevis (clawed frog,common platanna,platanna)
• Cellular location: Nucleus, nucleoplasm (By similarity): P56273
• Total number of polymer chains: 1
• Total formula weight: 10669.08

Authors

Janson, C.,Lukacs, C.,Kammlott, U.,Graves, B. (deposition date: 2013-02-12, release date: 2013-08-07, Last modification date: 2024-02-28)

Primary citation

Fry, D.C.,Wartchow, C.,Graves, B.,Janson, C.,Lukacs, C.,Kammlott, U.,Belunis, C.,Palme, S.,Klein, C.,Vu, B.
Deconstruction of a nutlin: dissecting the binding determinants of a potent protein-protein interaction inhibitor.
ACS Med Chem Lett, 4:660-665, 2013

PubMed Abstract: Protein-protein interaction (PPI) systems represent a rich potential source of targets for drug discovery, but historically have proven to be difficult, particularly in the lead identification stage. Application of the fragment-based approach may help toward success with this target class. To provide an example toward understanding the potential issues associated with such an application, we have deconstructed one of the best established protein-protein inhibitors, the Nutlin series that inhibits the interaction between MDM2 and p53, into fragments, and surveyed the resulting binding properties using heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR), surface plasmon resonance (SPR), and X-ray crystallography. We report the relative contributions toward binding affinity for each of the key substituents of the Nutlin molecule and show that this series could hypothetically have been discovered via a fragment approach. We find that the smallest fragment of Nutlin that retains binding accesses two subpockets of MDM2 and has a molecular weight at the high end of the range that normally defines fragments.

PubMed: 24900726
DOI: 10.1021/ml400062c

Experimental method

X-RAY DIFFRACTION (1.2 Å)