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. 2022 Dec 12;17(12):e0277770.
doi: 10.1371/journal.pone.0277770. eCollection 2022.

Pterin-based small molecule inhibitor capable of binding to the secondary pocket in the active site of ricin-toxin A chain

Ryota Saito  1   2 , Masaru Goto  3 , Shun Katakura  1 , Taro Ohba  3 , Rena Kawata  3 , Kazuki Nagatsu  3 , Shoko Higashi  1 , Kaede Kurisu  1 , Kaori Matsumoto  1 , Kouta Ohtsuka  1
Affiliations

Pterin-based small molecule inhibitor capable of binding to the secondary pocket in the active site of ricin-toxin A chain

Ryota Saito et al. PLoS One. .

Erratum in

Abstract

The Ricin toxin A chain (RTA), which depurinates an adenine base at a specific region of the ribosome leading to death, has two adjacent specificity pockets in its active site. Based on this structural information, many attempts have been made to develop small-molecule RTA inhibitors that simultaneously block the two pockets. However, no attempt has been successful. In the present study, we synthesized pterin-7-carboxamides with tripeptide pendants and found that one of them interacts with both pockets simultaneously to exhibit good RTA inhibitory activity. X-ray crystallographic analysis of the RTA crystal with the new inhibitor revealed that the conformational change of Tyr80 is an important factor that allows the inhibitors to plug the two pockets simultaneously.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Structures of pterin-7-carboxamides 1–4.
Scheme 1
Scheme 1. Synthesis of compounds 4a and 4b.
Reagents and conditions: (i) CH3I, K2CO3, dimethylformamide (DMF), 0°C to r.t.; (ii) 4-M HCl in 1,4-dioxane, r.t.; (iii) Boc-Phe-OH, PyBOP, iPr2NEt, DMF, r.t.; (iv) Fmoc-Gly-OH, PyBOP, iPr2NEt, DMF, r.t.; (v) piperidine, DMF, r.t.; (vi) 7-methoxycarbonylpterin, DBU, MeOH, r.t.
Fig 2
Fig 2
X-ray crystal structures of (A) 4a-RTA and (B) 4b-RTA complexes in surface representation styles. The ligands are colored in green, and the amino acid residues around the ligands are in blue except Tyr80 in magenta.
Fig 3
Fig 3. Interactions between 4b and RTA.
All interactions were detected and visualized by Discovery Studio Visualizer [11] in both 2D (right) and 3D (left) styles.
Fig 4
Fig 4. Comparison of the crystal structures of RTA-inhibitor complexes.
(A) crystal structure of 4b-RTA complex, (B) crystal structure of 2-RTA complex (PDB ID: 4HUP), (C) crystal structure of 3-RTA complex (PDB ID: 4HV7), and (D) crystal structure of RTAS complexed with the cyclic transition-model inhibitor (PDB ID: 3HIO). Images are drawn by Discovery Studio Visualizer [11].
See this image and copyright information in PMC

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