8J81

MDM2 bound with a peptoid

Summary for 8J81

• Entry DOI: 10.2210/pdb8j81/pdb
• Descriptor: 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)
• Functional Keywords: inhibitor, complex, peptoid, p53-binding protein, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 12608.13

Authors

Yokomine, M.,Fukuda, Y.,Ago, H.,Matsuura, H.,Ueno, G.,Nagatoishi, S.,Yamamoto, M.,Tsumoto, K.,Jumpei, M.,Sando, S. (deposition date: 2023-04-28, release date: 2024-05-01, Last modification date: 2024-11-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.35 Å)