Molecular Dissection of Mitogillin Reveals That the Fungal Ribotoxins Are a Family of Natural Genetically Engineered Ribonucleases

Kao, Richard; Davies, Julian

doi:10.1074/jbc.274.18.12576

Cited by 42 publications

(51 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, reinforcing the present observations regarding the crucial role of the stretch 11-16 of a-sarcin in ribosome recognition, a homologous region can be found in the elongation factor 2 (EF-2) from Saccharomyces cerevisiae [46]. The NH 2 -terminal b-hairpin of a-sarcin, containing residues 11-16, would have a counterpart in EF-2 that hence may be also involved in ribosome binding (Fig.…”

Section: Resultssupporting

confidence: 84%

Modeling the highly specific ribotoxin recognition of ribosomes

García-Mayoral¹,

Garcı́a-Ortega²,

Álvarez-García³

et al. 2005

FEBS Letters

View full text Add to dashboard Cite

The three-dimensional structures of the a-sarcin ribotoxin and its D(7-22) deletion mutant, both complexed with a 20-mer oligonucleotide mimicking the sarcin/ricin loop (SRL) of the ribosome, have been docked into the structure of the Halobacterium marismortui ribosome by fitting the nucleotide atomic coordinates into those of the ribosomal SRL. This study has revealed that two regions of the ribotoxin, residues 11-16 and 84-85, contact the ribosomal proteins L14 (residues 99-105) and L6 (residues 88-92), respectively. The first of these two ribotoxin regions appears to be crucial for its specific ribosome recognition.

show abstract

Section: Resultssupporting

confidence: 84%

Modeling the highly specific ribotoxin recognition of ribosomes

García-Mayoral¹,

Garcı́a-Ortega²,

Álvarez-García³

et al. 2005

FEBS Letters

View full text Add to dashboard Cite

show abstract

“…However, regarding the molecular bases for their roles, several questions remain open. (i) Structural (11) and biochemical data (12)(13)(14)(15) have implicated the importance of the interaction between loop 4 of the toxin with the bulged-G motif, formed by G4319, of the RNA (Fig. 1B).…”

Section: Dissection Of the High Rate Constant For The Binding Of A Rimentioning

confidence: 99%

Dissection of the high rate constant for the binding of a ribotoxin to the ribosome

Qin

Zhou

2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Restrictocin belongs to a family of site-specific ribonucleases that kill cells by inactivating the ribosome. The restrictocin–ribosome binding rate constant was observed to exceed 1010 M−1 s−1. We have developed a transient-complex theory to model the binding rates of protein–protein and protein–RNA complexes. The theory predicts the rate constant as ka = ka0 exp(−ΔGel*/kBT), where ka0 is the basal rate constant for reaching the transient complex, located at the outer boundary of the bound state, by random diffusion, and ΔGel* is the average electrostatic interaction free energy of the transient complex. Here, we applied the transient-complex theory to dissect the high restrictocin–ribosome binding rate constant. We found that the binding rate of restrictocin to the isolated sarcin/ricin loop is electrostatically enhanced by ≈300-fold, similar to results found in other protein–protein and protein–RNA complexes. The ribosome provides an additional 10,000-fold rate enhancement because of two synergistic mechanisms afforded by the distal regions of the ribosome. First, they provide additional electrostatic attraction with restrictocin. Second, they reposition the transient complex into a region where local electrostatic interactions of restrictocin with the sarcin/ricin loop are particularly favorable. Our calculations rationalize a host of experimental observations and identify a strategy for designing proteins that bind their targets with high speed.

show abstract

“…A few fungal ribonucleases are also known to have antitumor activity (46). Specifically, the Aspergillus ribonucleases ␣-sarcin (47), mitogillin (48), restrictocin (49), and Asp-fl (50) kill cells by cleaving a specific phosphodiester bond in 28 S rRNA, thereby disrupting the ribosome and impairing protein biosynthesis (51).…”

Section: Quality Of Final Proteinmentioning

confidence: 99%