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

Journal Article · Tue Jan 12 04:00:00 EST 2010 · Proc. Natl. Acad. Sci. USA

DOI:https://doi.org/10.1073/pnas.0911606106· OSTI ID:1006028

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

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{sub 2}O nucleophile. Catalytic forces originate primarily from leaving group activation evident in both RTA and SAP in complex with transition state analogues.

• Research Organization: Argonne National Laboratory (ANL)
• Sponsoring Organization: USDOE
• OSTI ID: 1006028
• Journal Information: Proc. Natl. Acad. Sci. USA, Journal Name: Proc. Natl. Acad. Sci. USA Journal Issue: (48) ; 12, 2009 Vol. 106; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
ADENINES
ADENOSINE
ARGININE
CATALYSIS
CRYSTAL STRUCTURE
DEATH
GEOMETRY
GUANINE
POLARIZATION
PROTEINS
STABILIZATION
SYNTHESIS