8J81

MDM2 bound with a peptoid

8J81 の概要

• エントリーDOI: 10.2210/pdb8j81/pdb
• 分子名称: E3 ubiquitin-protein ligase Mdm2, (2S)-2-[[(2S)-2-[(6-chloranyl-1H-indol-3-yl)methyl-[(2S)-2-[[(2S)-2-[ethanoyl-(phenylmethyl)amino]propanoyl]-methyl-amino]propanoyl]amino]propanoyl]-methyl-amino]-N-(3,3-dimethylbutyl)-N-[(2S)-1-oxidanylidene-1-piperazin-1-yl-propan-2-yl]propanamide, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, complex, peptoid, p53-binding protein, ligase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12608.13

構造登録者

Yokomine, M.,Fukuda, Y.,Ago, H.,Matsuura, H.,Ueno, G.,Nagatoishi, S.,Yamamoto, M.,Tsumoto, K.,Jumpei, M.,Sando, S. (登録日: 2023-04-28, 公開日: 2024-05-01, 最終更新日: 2024-11-27)

主引用文献

Yokomine, M.,Morimoto, J.,Fukuda, Y.,Ueda, T.,Takeuchi, K.,Umezawa, K.,Ago, H.,Matsuura, H.,Ueno, G.,Senoo, A.,Nagatoishi, S.,Tsumoto, K.,Sando, S.
A high-resolution structural characterization and physicochemical study of how a peptoid binds to an oncoprotein MDM2.
Chem Sci, 15:7051-7060, 2024

PubMed Abstract: Peptoids are a promising drug modality targeting disease-related proteins, but how a peptoid engages in protein binding is poorly understood. This is primarily due to a lack of high-resolution peptoid-protein complex structures and systematic physicochemical studies. Here, we present the first crystal structure of a peptoid bound to a protein, providing high-resolution structural information about how a peptoid binds to a protein. We previously reported a rigid peptoid, oligo(-substituted alanine) (oligo-NSA), and developed an oligo-NSA-type peptoid that binds to MDM2. X-ray crystallographic analysis of the peptoid bound to MDM2 showed that the peptoid recognizes the MDM2 surface predominantly through the interaction of the -substituents, while the main chain acts as a scaffold. Additionally, conformational, thermodynamic, and kinetic analysis of the peptoid and its derivatives with a less rigid main chain revealed that rigidification of the peptoid main chain contributes to improving the protein binding affinity. This improvement is thermodynamically attributed to an increased magnitude of the binding enthalpy change, and kinetically to an increased association rate and decreased dissociation rate. This study provides invaluable insights into the design of protein-targeting peptoids.

PubMed: 38756815
DOI: 10.1039/d4sc01540a

実験手法

X-RAY DIFFRACTION (1.35 Å)