Issue 19, 2024

A high-resolution structural characterization and physicochemical study of how a peptoid binds to an oncoprotein MDM2

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(N-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 N-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.

Graphical abstract: A high-resolution structural characterization and physicochemical study of how a peptoid binds to an oncoprotein MDM2

Supplementary files

Article information

Article type
Edge Article
Submitted
05 mar 2024
Accepted
16 apr 2024
First published
19 apr 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2024,15, 7051-7060

A high-resolution structural characterization and physicochemical study of how a peptoid binds to an oncoprotein MDM2

M. Yokomine, J. Morimoto, Y. Fukuda, T. Ueda, K. Takeuchi, K. Umezawa, H. Ago, H. Matsuura, G. Ueno, A. Senoo, S. Nagatoishi, K. Tsumoto and S. Sando, Chem. Sci., 2024, 15, 7051 DOI: 10.1039/D4SC01540A

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