Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The G domain and domain II in the crystal structure of Thermus thermophilus elongation factor G (EF-G) were compared with the homologous domains in Thermus aquaticus elongation factor Tu (EF-Tu). Sequence alignment derived from the structural superposition was used to define conserved sequence elements in domain II. These elements and previously known conserved sequence elements in the G domain were used to guide the alignment of the sequences of Sulfolobus acidocaldarius elongation factor 2, human elongation factor 2, and Escherichia coli initiation factor 2 and release factor 3 to the aligned sequences of EF-G and EF-Tu. This alignment, which deviates from previously published alignments, has evolutionary implications and leads to alternative interpretations of biochemical data concerning the interaction of elongation factors with the alpha-sarcin/ricin region of the ribosome. A single conserved sequence motif in domain II was identified and used to further characterize the GTPase subfamily of translation factors and related proteins. It was shown that the motif is found in most if not all the members of the family. Apparently, the common characteristic of these GTPases is an extensive consensus structural unit that possibly accounts for a similar interaction with the ribosome and is composed of two domains homologous to the G domain and domain II in EF-Tu and EF-G.
J Mol Evol 1995 Dec
PMID:Structure-based sequence alignment of elongation factors Tu and G with related GTPases involved in translation. 858 8

Ricin A-chin and alpha-sarcin are ribotoxins that inactivate eukaryotic ribosomes by modifying 28 S rRNA; ricin A-chain is an RNA N-glycosidase that depurinates the adenosine at position 4324 and alpha-sarcin is a ribonuclease that cleaves the phosphodiester bond on the 3' side of the adjacent guanosine (at position 4325). In cartoons of the secondary structure these two residues are seen to be embedded in a 17 base single-stranded loop over a seven base-pair helix. However, NMR spectroscopy of an oligoribonucleotide, a 29-mer that mimics the sarcin/ricin domain, indicates that the RNA has a compact conformation in which the guanosine at the position analogous to 4319 in 28 S rRNA is bulged out of what otherwise is an extended A-form helix. Since similar structural irregularities are used by proteins to bind to RNA, we have tested the effect of mutations of the bulged guanosine on recognition and covalent modification of the RNA by ricin A-chain and by alpha-sacrin. For the test a synthetic oligoribonucletide, a 35-mer, was used; the mutations were the deletion, the transition to adenosine, and the transversion to cytidine and uridine of the guanosine that is the analog of G4319. Each of the four mutations abolished cleavage og the RNA by alpha-sacrin, where depurination by ricin A-chain was little affected. Thus G4319 is an identity element for alpha-sacrin recognition. Analysis of the effect of alpha-sacrin on variant oligoribonucleotides in which additional bases were inserted between the identity element guanosine and the site of catalysis suggest that on binding to the RNA the toxin uses the guanosine for orientation and then cleaves at a fixed distance and at a fixed position in space.
J Mol Biol 1996 Mar 15
PMID:Determination of the 28 S ribosomal RNA identity element (G4319) for alpha-sarcin and the relationship of recognition to the selection of the catalytic site. 860 35

The interaction between "R/S domain" of rat 28S rRNA and ribosome-inactivating proteins (RIPs) has been studied by blocking the action site of RIPs on "R/S domain" of 28S rRNA with fusidic acid or S100. Fusidic acid alone could form stable complexes with rat ribosomes and block the action site of RNA N-glycosidases. incubation of fusidic acid and S100 or GDP with ribosomes could also protect ribosomes from the action of ricin A-chain. However, different effect of fusidic acid, S100 an dGDP was observed when alpha-sarcin was used. Fusidic acid alone could not block the action site of alpha-sarcin. Fusidic acid together with the elongation factors in S100 could block the action site of alpha-sarcin. These results are consistent with the previous report that ricin A-chain and alpha-sarcin recognized different conformation of "R/S domain" in rat 28S rRNA.
Biochem Mol Biol Int 1995 Nov
PMID:The interaction between "R/S domain" of rat 28S ribosomal RNA and ribosome-inactivating proteins investigated by fusidic acid. 862 93

Ribosomal function in protein synthesis requires dynamic flexibility of the ribosomal structure. The two translational inhibitors derived from seeds of ricin and barley destroy the dynamic properties of the ribosome by selective depurination of A4256 in the phylogenetically conserved alpha-sarcin/ricin loop of mouse 28 S rRNA. As the alpha-sarcin/ricin loop is involved in binding of elongation factors to the ribosome, depurination blocks the protein synthesis elongation cycle. Depurination by the barley translational inhibitor (BTI) mainly effects eEF-1 alpha related functions, while ricin interferes with the interaction of eEF-2 with the ribosome. Analysis of the ribosomal structure after inhibitor shows that the accessibility of the rRNAs for single-strand-specific chemical modification was altered. Reactivity changes were seen in domains I, II and V of 28 S rRNA and in 5 S rRNA. A majority of the reactivity changes were found in putative functional regions of the rRNAs, such as the regions involved in peptidyltransferase activity, subunit interaction and in the binding of elongation factors. Most of the observed structural changes made the rRNAs less accessible for chemical modification, suggesting that the ribosomal particles became less flexible after inhibitor treatment. Moreover, the modification patterns obtained from the two inhibitor-treated ribosomal particles were only partly overlapping, indicating that the structure of the large ribosomal subunit differed after ricin and BTI treatment. Surprisingly, depurination in the alpha-sarcin/ricin loop of 28 S rRNA also affected the structure of the 3' major domain in 18 S rRNA.
J Mol Biol 1996 May 31
PMID:Depurination of A4256 in 28 S rRNA by the ribosome-inactivating proteins from barley and ricin results in different ribosome conformations. 864 51

The synthesis of IgE antibodies by B cells is the first in a series of steps resulting in an allergic response. To eliminate IgE-bearing B cells and thereby prevent IgE production, we have developed an immunotoxin (ITA) composed of the non-anaphylactic 84.1c anti-mouse IgE mAb and the A chain of ricin (ricin A). This ITA specifically inhibited the induction of IgE synthesis by lipopolysaccharide plus interleukin-4 (LPS + IL-4) in vitro, and antigen-specific IgE production in vivo in adult mice. A single dose of anti-IgE ITA, given within a week (either before or after) of antigen challenge completely abolished antigen-specific primary IgE responses. No IgE production was seen for 2 months after ITA treatment. Following antigenic re-challenge, a suppressed secondary response (over 50% reduction) was still seen in the ITA-treated mice, 100 days after immunization. The results of this study demonstrate the potential use of anti-IgE toxin conjugates for the suppression of periodic (seasonal) allergic outbreaks.
Mol Immunol 1996 Feb
PMID:Prolonged inhibition of IgE production in mice following treatment with an IgE-specific immunotoxin. 864 45

Ricin has been shown to induce oxidative stress in the livers of mice in vivo. These studies examined ricin-induced hepatic microsomal lipid peroxidation in mice, and the modulation thereof by iron and desferrioxamine. In addition, the studies investigated the production of superoxide anion by microsomes, mitochondria, and macrophages. Ricin (25 micrograms/kg, in vivo) increased microsomal lipid peroxidation by approximately 1.8-fold relative to control animals. This effect was abrogated by adding desferrioxamine to the microsomes. Fe2+ increased lipid peroxidation approximately 15-fold and 5-fold when added to microsomes from control and ricin-treated animals, respectively. Adding ricin to microsomes from control animals, however, decreased lipid peroxidation in a concentration-dependent manner. Desferrioxamine decreased lipid peroxidation by 47% and 64% in the absence and presence of ricin (5 micrograms/ml), respectively. Ricin, added to mitochondria from untreated animals decreased lipid peroxidation by 26% and 17% in the presence and absence of Fe2+, respectively. The administration of ricin (5 and 25 micrograms/kg) to mice increased microsomal, mitochondrial and macrophage superoxide anion production, in a dose-dependent fashion. The results suggest that iron mediated production of superoxide anion may be involved in the process of oxidative stress induced by ricin.
Res Commun Mol Pathol Pharmacol 1996 Apr
PMID:Role of iron in ricin-induced lipid peroxidation and superoxide production. 873 32

Ricin A-chain is a cytotoxic RNA N-glycosidase that inactivates eukaryotic ribosomes by depurinating the adenosine at position 4324 in 28S rRNA. The enzyme retains its specificity when a synthetic oligoribonucleotide (a 35-mer) that mimics the structure at the site of action is the substrate. However, covalent modification by ricin A-chain of the oligoribonucleotide but not of ribosomes, depends on the simultaneous presence of a divalent cation and a chelating agent.
Biochem Mol Biol Int 1996 May
PMID:Dependence of depurination of oligoribonucleotides by ricin A-chain on divalent cations and chelating agents. 879 55

The new type 2 RIPs ebulin l, nigrin b and nigrin f present in Sambucus display toxicity to HELA cells several orders of magnitude lower than that displayed by ricin. Despite N-terminal amino acid homology between the three RIPs in both the A and the B chains, these compounds display very different degrees of toxicity to HELA cells that does not seem to be paralleled by immunologic correlations. It is suggested that small changes in the protein structure are most probably responsible for the different degrees of toxicity.
Cell Mol Biol (Noisy-le-grand) 1996 Jun
PMID:Differential sensitivity of HELA cells to the type 2 ribosome-inactivating proteins ebulin l, nigrin b and nigrin f as compared with ricin. 882 2

Purified beef and rabbit liver tRNA(Trp), but not yeast tRNA(Trp), increase the in vitro inactivation of eukaryotic ribosomes by gelonin, a ribosome-inactivating protein with RNA-N-glycosidase activity on 28S rRNA. Aminoacylation and stepwise trimming of the 3'-end of bovine tRNA(Trp) affect the cofactor activity, the most active species being that shortened by the last two nucleotides. ATP only moderately increases the activity of purified mammalian tRNA(Trp) and in this increase the cognate aminoacyl-tRNA synthetase apparently has no role. Mobility shift experiments indicate that bovine tRNA(Trp) binds both to ribosomes and to gelonin and favours the dissociation of gelonin from ribosomes.
Biochem Mol Biol Int 1996 Sep
PMID:tRNA(Trp) as cofactor of gelonin, a ribosome-inactivating protein with RNA-N-glycosidase activity. Features required for the cofactor activity. 888 84

The primary structure has been determined for PD-S2, a new type 1 ribosome-inactivating protein (RIP), isolated from the seeds of Phytolacca dioica L. PD-S2 has 265 amino-acid residues, and a molecular mass of 29586 Da. The polypeptide chain contains four amino-acid residues more than PAP-S, a type-I RIP isolated from the seeds of the taxonomically related plant Phytolacca americana L. We have compared the amino-acid sequence of PD-S2 with those of two other RIPs with known three-dimensional structure: PAP-S and ricin A-chain (RTA), the active chain of the best known type-2 RIP. This analysis shows an identity of 76% and 33% with PAP-S and RTA respectively, and a similarity of 82% and 54%. Comparison with the PAP sequence, isolated from leaves of P. americana, shows an even higher identity (80%) and similarity (87%). Furthermore, the amino-acid residues reported in other RIPs to be invariant and participate in the definition of the active site (Tyr-76, Tyr-127, Glu-179, Arg-182 and Trp-211; PD-S2 numbering) are all present. Asn-74, Arg-138, Gln-175, and Glu-208 are also conserved, while Asn-209 is substituted by Glu, all residues located in the active-site cleft of RIPs (Tahirov, T.H., Lu, T.-H., Liaw, Y.-C., Chen, J.L. and Lin, J.Y. (1995) Crystal structure of abrin-a at 2.14 A, J. Mol. Biol. 250, 354-367). The polypeptide chain of PD-S2 contains two N-glycosylation sites at Asn-112 and Asn-120, the second of which appears to be linked to sugars. Like PAP-S, PD-S2 does not contain free sulfhydryl groups. The four cysteinyl residues of the two proteins have corresponding sequence positions, most likely with identical S-S pairing.
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PMID:Complete amino-acid sequence of PD-S2, a new ribosome-inactivating protein from seeds of Phytolacca dioica L. 907 24


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