Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins.

Proceedings of the National Academy of Sciences of the United States of America
Meng-Chiao HoVern L Schramm

Abstract

Ricin A-chain (RTA) and saporin-L1 (SAP) catalyze adenosine depurination of 28S rRNA to inhibit protein synthesis and cause cell death. We present the crystal structures of RTA and SAP in complex with transition state analogue inhibitors. These tight-binding inhibitors mimic the sarcin-ricin recognition loop of 28S rRNA and the dissociative ribocation transition state established for RTA catalysis. RTA and SAP share unique purine-binding geometry with quadruple pi-stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the pi-stack provides cationic polarization and enhanced leaving group ability to the susceptible adenine. Common features of these ribosome-inactivating proteins include adenine leaving group activation, a remarkable lack of ribocation stabilization, and conserved glutamates as general bases for activation of the H(2)O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues.

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Citations

Dec 25, 2012·ACS Chemical Biology·Vern L Schramm
Dec 12, 2012·Journal of Medicinal Chemistry·Ryota SaitoJon D Robertus
Feb 10, 2011·The Journal of Biological Chemistry·Jianxing DaiYajun Guo
May 27, 2015·Toxins·Joachim SchrotMatthias F Melzig
Feb 18, 2016·ACS Chemical Biology·Hongling YuanVern L Schramm
Jun 12, 2010·Physiologia Plantarum·Andrea TartariniLaura Spanò
Sep 28, 2013·Virulence·Matthew J WalshGuillaume M Hautbergue
Nov 9, 2016·European Journal of Medicinal Chemistry·Jennifer M MasonVern L Schramm
Sep 8, 2017·Journal of Biochemical and Molecular Toxicology·Roy E BarnewallCarrie A Howland
Dec 7, 2018·The FEBS Journal·Harsh BansiaSuryanarayanarao Ramakumar
May 16, 2019·Chemical Society Reviews·Wei TangXiaoyuan Chen
Mar 17, 2015·Doklady. Biochemistry and Biophysics·E V LoukianovYu V Kozlov
Jun 9, 2019·Toxins·Jeroen De ZaeytijdEls J M Van Damme
Sep 3, 2014·Organic & Biomolecular Chemistry·Alexander C Drohat, Atanu Maiti
Nov 10, 2011·Toxins·Karl JashewayJon D Robertus
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May 1, 2019·Toxins·Przemysław GrelaMarek Tchórzewski
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Feb 3, 2021·Journal of Biomolecular Structure & Dynamics·Elton José Ferreira ChavesGerd Bruno Rocha
Jul 13, 2020·International Journal of Biological Macromolecules·Xiaojiao FanTengchuan Jin
May 20, 2020·ACS Infectious Diseases·Xiao-Ping LiNilgun E Tumer
Oct 11, 2012·ACS Medicinal Chemistry Letters·Jeff M PruetJon D Robertus
Oct 20, 2018·Chemical Reviews·Vern L Schramm
Jun 7, 2011·European Journal of Medicinal Chemistry·Jeff M PruetJon D Robertus

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