4J7E

The 1.63A crystal structure of humanized Xenopus MDM2 with a nutlin fragment, RO5524529

4J7E の概要

• エントリーDOI: 10.2210/pdb4j7e/pdb
• 関連するPDBエントリー: 4IPF 4J3E 4J74 4J7D
• 分子名称: E3 ubiquitin-protein ligase Mdm2, [(4S,5R)-4,5-bis(4-chlorophenyl)-2,4,5-trimethyl-4,5-dihydro-1H-imidazol-1-yl]{4-[3-(methylsulfonyl)propyl]piperazin-1-yl}methanone, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: protein-protein interaction, ligase-antagonist complex, mdm2, e3 ubiquitin ligase, p53, imidazoline, nucleus, ligase/antagonist
• 由来する生物種: Xenopus laevis (clawed frog,common platanna,platanna)
• 細胞内の位置: Nucleus, nucleoplasm (By similarity): P56273
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 10624.23

構造登録者

Janson, C.,Lukacs, C.,Graves, B. (登録日: 2013-02-13, 公開日: 2013-08-07, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.63 Å)