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Conformational change in ricin toxin A-Chain: A critical factor for inhibitor binding to the secondary pocket

Ricin toxin A-chain (RTA), a toxic protein from Ricinus communis, inactivates ribosomes to induce toxicity. The active site of RTA consists of two binding pockets. Many studies have focused on developing RTA inhibitors that can simultaneously bind to these critical pockets; however, almost all the i...

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Published in:Biochemical and biophysical research communications 2022-10, Vol.627, p.1-4
Main Authors: Goto, Masaru, Higashi, Shoko, Ohba, Taro, Kawata, Rena, Nagatsu, Kazuki, Suzuki, Saori, Anslyn, Eric V., Saito, Ryota
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cited_by cdi_FETCH-LOGICAL-c399t-cae12842555998516e038e31738ea3b20f33f29ac2b1ca9b6e2b1b2b97b35bc53
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container_title Biochemical and biophysical research communications
container_volume 627
creator Goto, Masaru
Higashi, Shoko
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Kawata, Rena
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Saito, Ryota
description Ricin toxin A-chain (RTA), a toxic protein from Ricinus communis, inactivates ribosomes to induce toxicity. The active site of RTA consists of two binding pockets. Many studies have focused on developing RTA inhibitors that can simultaneously bind to these critical pockets; however, almost all the inhibitors developed so far interact with only one pocket. In the present study, we discovered that pterin-7-carboxamides with aromatic l-amino acid pendants interacted with the active site of the enzyme in a 2-to-1 mode, where one inhibitor molecule bound to the primary pocket and the second one entered the secondary pocket in the active site of RTA. X-ray crystallographic analysis of inhibitor/RTA complexes revealed that the conformational changes of Tyr80 and Asn122 in RTA were critical for triggering the entry of inhibitor molecules into the secondary pocket of the RTA active site. •Ricin toxin A chain (RTA) has two specific pockets in its active site.•No small molecular inhibitor was reported to bind to the secondary pocket of RTA.•Some pterin-7-carboxamides bind to the RTA active site in a 2-to-1 mode.•This is the first exaple of small molecules binding to the secondary pocket of RTA.•Movements of Tyr80 and Asn122 triggers the crucial binding of inhibitors to RTA.
doi_str_mv 10.1016/j.bbrc.2022.08.008
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title Conformational change in ricin toxin A-Chain: A critical factor for inhibitor binding to the secondary pocket
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