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The 1.63A crystal structure of humanized Xenopus MDM2 with a nutlin fragment, RO5524529The 1.63A crystal structure of humanized Xenopus MDM2 with a nutlin fragment, RO5524529
Structural highlights
FunctionMDM2_XENLA E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degration by the proteasome (By similarity). Publication Abstract from PubMedProtein-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. Deconstruction of a nutlin: dissecting the binding determinants of a potent protein-protein interaction inhibitor.,Fry DC, Wartchow C, Graves B, Janson C, Lukacs C, Kammlott U, Belunis C, Palme S, Klein C, Vu B ACS Med Chem Lett. 2013 May 24;4(7):660-5. doi: 10.1021/ml400062c. eCollection, 2013 Jul 11. PMID:24900726[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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