Crystal structure of ricin toxin A chain complexed with a highly potent pterin-based small-molecular inhibitor

Abstract

Ricin toxin A chain (RTA), from Ricinus communis, is a deadly protein that inactivates ribosomes by degrading an adenine residue at position 4324 in 28S rRNA. Recently, we have demonstrated that pterin-7-carboxamides with peptide pendants were potent RTA inhibitors. Among these, N-(pterin-7-carbonyl)glycyl-L-tyrosine (7PCGY) is the most potent RTA inhibitor as a small organic molecule. However, despite this fascinating inhibitory activity, the mode of interaction of 7PCGY with RTA remains elusive. This study aimed to elucidate the factors responsible for the high RTA inhibitory activity of 7PCGY based on X-ray crystallographic analysis. Herein, we report the successfully resolved X-ray crystal structure of 7PCGY/RTA complexes, revealing that the interaction between the phenolic hydroxy group in 7PCGY and Asn78 of RTA through a hydrogen bonding and the conformational change of Tyr80 and Asn122 are responsible for the high RTA inhibitory activity of 7PCGY.

Keywords:

• Ricin toxin A chain
• ricin toxin A chain inhibitor
• pterin-7-carboxamide
• X-ray crystallography

Acknowledgement

We would like to thank the staff of the Photon Factory for their assistance with the data collection. The authors would also like to thank Editage (www.editage.jp) for the English language editing.

Ethical statement

This study was performed with the approval of the Photon Factory Program Advisory Committee (proposal No. 2018G520 and 2022G603).

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This research was supported by JSPS KAKENHI Grant Number 19K05699 and Japan Society for the Promotion of Science.