4UD7

Structure of the stapled peptide YS-02 bound to MDM2

4UD7 の概要

• エントリーDOI: 10.2210/pdb4ud7/pdb
• 関連するPDBエントリー: 4UE1
• 分子名称: MDM2, YS-02 (3 entities in total)
• 機能のキーワード: lyase, mdm2, stapled peptide, p53
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Nucleus, nucleoplasm: Q00987
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 58683.08

構造登録者

Tan, Y.S.,Reeks, J.,Brown, C.J.,Jennings, C.E.,Eapen, R.S.,Tng, Q.S.,Thean, D.,Ying, Y.T.,Gago, F.J.F.,Lane, D.P.,Noble, M.E.M.,Verma, C. (登録日: 2014-12-08, 公開日: 2016-01-13, 最終更新日: 2023-12-20)

主引用文献

Tan, Y.S.,Reeks, J.,Brown, C.J.,Thean, D.,Ferrer Gago, F.J.,Yuen, T.Y.,Goh, E.T.,Lee, X.E.,Jennings, C.E.,Joseph, T.L.,Lakshminarayanan, R.,Lane, D.P.,Noble, M.E.,Verma, C.S.
Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design.
J Phys Chem Lett, 7:3452-3457, 2016

PubMed Abstract: Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated. Here, we report the use of benzenes as probe molecules in ligand-mapping MD (LMMD) simulations to predict the existence of two novel binding sites on the surface of the oncoprotein MDM2. One of them was serendipitously confirmed by biophysical assays and X-ray crystallography to be important for the binding of a new family of hydrocarbon stapled peptides that were specifically designed to target the other putative site. These results highlight the predictive power of LMMD and suggest that predictions derived from LMMD simulations can serve as a reliable basis for the identification of novel ligand binding sites in structure-based drug design.

PubMed: 27532490
DOI: 10.1021/acs.jpclett.6b01525

実験手法

X-RAY DIFFRACTION (1.6 Å)