1Z1M

NMR structure of unliganded MDM2

1Z1M の概要

• エントリーDOI: 10.2210/pdb1z1m/pdb
• NMR情報: BMRB: 6612
• 分子名称: Ubiquitin-protein ligase E3 Mdm2 (1 entity in total)
• 機能のキーワード: peptide-binding groove, psudosymmetry, alpha-beta domains, ligase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus, nucleoplasm: Q00987
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13571.59

構造登録者

Uhrinova, S.,Uhrin, D.,Powers, H.,Watt, K.,Zheleva, D.,Fischer, P.,McInnes, C.,Barlow, P.N. (登録日: 2005-03-04, 公開日: 2005-06-28, 最終更新日: 2024-05-29)

主引用文献

Uhrinova, S.,Uhrin, D.,Powers, H.,Watt, K.,Zheleva, D.,Fischer, P.,McInnes, C.,Barlow, P.N.
Structure of Free MDM2 N-terminal Domain Reveals Conformational Adjustments that Accompany p53-binding
J.Mol.Biol., 350:587-598, 2005

PubMed Abstract: Critical to the inhibitory action of the oncogene product, MDM2, on the tumour suppressor, p53, is association of the N-terminal domain of MDM2 (MDM2N) with the transactivation domain of p53. The structure of MDM2N was previously solved with a p53-derived peptide, or small-molecule ligands, occupying its binding cleft, but no structure of the non-liganded MDM2N (i.e. the apo-form) has been reported. Here, we describe the solution structure and dynamics of apo-MDM2N and thus reveal the nature of the conformational changes in MDM2N that accompany binding of p53. The new structure suggests that p53 effects displacement of an N-terminal segment of apo-MDM2N that occludes access to the shallow end of the p53-binding cleft. MDM2N must also undergo an expansion upon binding, achieved through a rearrangement of its two pseudosymetrically related sub-domains resulting in outward displacements of the secondary structural elements that comprise the walls and floor of the p53-binding cleft. MDM2N becomes more rigid and stable upon binding p53. Conformational plasticity of the binding cleft of apo-MDM2N could allow the parent protein to bind specifically to several different partners, although, to date, all the known liganded structures of MDM2N are highly similar to one another. The results indicate that the more open conformation of the binding cleft of MDM2N observed in structures of complexes with small molecules and peptides is a more suitable one for ligand discovery and optimisation.

PubMed: 15953616
DOI: 10.1016/j.jmb.2005.05.010

実験手法

SOLUTION NMR