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

Meng Chiao Ho, Matthew B. Sturm, Steven C. Almo, Vern L. Schramm

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 π-stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the π-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 H2O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues.

Original languageEnglish (US)
Pages (from-to)20276-20281
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number48
DOIs
StatePublished - Dec 1 2009

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Ribosome Inactivating Proteins
Ricin
Adenine
Glutamates
Guanine
Catalysis
Adenosine
Arginine
Cause of Death
Cell Death
saporin
Proteins

Keywords

  • Depurination
  • Ricin toxin A-chain
  • Saporin-L1
  • Sarcin-ricin loop

ASJC Scopus subject areas

  • General

Cite this

Transition state analogues in structures of ricin and saporin ribosome-inactivating proteins. / Ho, Meng Chiao; Sturm, Matthew B.; Almo, Steven C.; Schramm, Vern L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 48, 01.12.2009, p. 20276-20281.

Research output: Contribution to journalArticle

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AU - Almo, Steven C.

AU - Schramm, Vern L.

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N2 - 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 π-stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the π-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 H2O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues.

AB - 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 π-stacking interactions between adjacent adenine and guanine bases and 2 conserved tyrosines. An arginine at one end of the π-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 H2O 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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