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 constants of sin-anti-equilibrium in aqueous solution of model inhibitors of peptidyltransferase center of ribosomes: 3'-amino-3'-deoxadenosine-5'-phosphate, 3'-N-glycinamido-3'-deoxyadenosine, 3'-(N-formyl-L-methionynamido)-3'-deoxyadenosine-5'-phosphate and 3'-(n-formylglycinamido)-3'-deoxyadenosine-5'-phosphate were determined using the measurements of spin-lattice relaxation times. All compounds have similar conformation possibilities of the nucleotide component. The possibilities of correlation between the biological activity of these compounds and their conformation in aqueous solution are discussed.
Mol Biol (Mosk)
PMID:[Model substates and inhibitors of the peptidyltransferase center of ribosomes. Conformational possibilities in aqueous solution]. 709 57

The role of ribosomal RNA in maintaining the accuracy of translation has been investigated genetically by selecting for rRNA mutations that promoted frameshifting at a specific site in a reporter gene in Escherichia coli. Mutations were recovered in two different regions of 23 S rRNA and each promoted readthrough of stop codons as well as increasing the levels of frameshifting. The first group of mutations was in a small stem loop (the 1916 loop) in domain IV of 23 S rRNA. This stem-loop has been mapped to the subunit interface of the ribosome, close to the decoding center on the 30 S subunit. The second group of mutations was in helix 89, one of the helices emerging from the central loop of domain V. Helix 89 has been implicated in subunit-subunit interactions and peptidyltransferase activity, and it is proposed that mutations in helix 89 influence the accuracy of decoding by affecting the interaction of the CCA end of the tRNA with the peptidyltransferase center.
J Mol Biol 1995 Dec 15
PMID:The involvement of two distinct regions of 23 S ribosomal RNA in tRNA selection. 750 Mar 54

Mutants of Escherichia coli defective in the HemA protein grow extremely poorly as the result of heme deficiency. A novel hemA mutant was identified whose rate of growth was dramatically enhanced by addition to the medium of low concentrations of translational inhibitors, such as chloramphenicol and tetracycline. This mutant (H110) carries mutation at position 314 in the hemA gene, which resulted in diminished activity of the encoded protein. Restoration of growth of H110 upon addition of the drugs mentioned above was due to activation of the synthesis of porphyrin. However, this activation was not characteristic exclusively of cells with this mutant hemA gene since it was also observed in a heme-deficient strain bearing the wild-type hemA gene. The activation did not depend on the promoter activity of the hemA gene, as indicated by studies with fusion genes. It appears that partial inhibition of protein synthesis via inhibition of peptidyltransferase can promote the synthesis of porphyrin by providing an increased supply of glutamyl-tRNA for porphyrin synthesis. Glutamyl-tRNA is the common substrate for peptidyltransferase and HemA.
Mol Gen Genet 1995 Nov 15
PMID:Partial inhibition of protein synthesis accelerates the synthesis of porphyrin in heme-deficient mutants of Escherichia coli. 750 Sep 34

Isolated 50 S ribosomal subunits from the halophilic archaebacterium Haloarcula marismortui were treated in situ with the homobifunctional and cleavable crosslinking reagent dithiobis(succinimidyl propionate) (12 A). Several crosslinked complexes were obtained. Among these were the protein pairs HmaL4-HL29 and HmaL18-HL31; HL29 and HL31 are ribosomal proteins without any equivalent in eubacterial ribosomes. The crosslinked protein pairs were isolated on a preparative scale by combining conventional ion-exchange chromatography and reverse phase high-pressure liquid chromatography. The monomeric proteins involved in crosslink formation were unambiguously identified by two-dimensional gel electrophoresis and N-terminal or internal protein sequencing. Due to the homology between HmaL4 and HmaL18 and their Escherichia coli counterparts, and the roughly known location of these proteins within the 50 S subunit, our results demonstrate that HL29 is probably located in the centre of the large subunit in the vicinity of the peptidyltransferase domain, whereas HL31 must be situated within the central protuberance close to the region of the 5 S RNA.
J Mol Biol 1993 Jul 20
PMID:Localization of proteins HL29 and HL31 from Haloarcula marismortui within the 50 S ribosomal subunit by chemical crosslinking. 834 27

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

Electrostatic and structural properties of a set of beta-lactam, gamma-lactam and nonlactam compounds have been analyzed and compared with those of a model of the natural substrate D-alanyl-D-alanine for the carboxy- and transpeptidase enzymes. This first comparison of the electrostatic properties has been based on a distributed multipole analysis of high-quality ab initio wave functions of the substrate and potential antibiotics. The electrostatic similarity of the substrate and active compounds is apparent, and contrasts with the electrostatic properties of the noninhibitors. This has been quantified to give a reasonable correlation with the MIC (Minimum Concentration for Inhibition) and with kinetic data (k2/K) in accordance with the model for interaction of the lactam compounds with DD-peptidase. These correlations provide a better prediction of antibacterial activity than purely structural criteria.
J Comput Aided Mol Des 1996 Apr
PMID:On the electrostatic and steric similarity of lactam compounds and the natural substrate for bacterial cell-wall biosynthesis. 874 Oct 15

FtsI, also known as penicillin-binding protein 3, is a transpeptidase required for the synthesis of peptidoglycan in the division septum of the bacterium, Escherichia coli. FtsI has been estimated to be present at about 100 molecules per cell, well below the detection limit of immunoelectron microscopy. Here, we confirm the low abundance of FtsI and use immunofluorescence microscopy, a highly sensitive technique, to show that FtsI is localized to the division site during the later stages of cell growth. FtsI was also sometimes observed at the cell pole; polar localization was not anticipated and its significance is not known. We conclude (i) that immunofluorescence microscopy can be used to localize proteins whose abundance is as low as approximately 100 molecules per cell; and (ii) that spatial and temporal regulation of FtsI activity in septum formation is achieved, at least in part, by timed localization of the protein to the division site.
Mol Microbiol 1997 Aug
PMID:Localization of the Escherichia coli cell division protein Ftsl (PBP3) to the division site and cell pole. 937 97

Macrolides are bacteriostatic antibiotics which interfere with the peptidyltransfer function of the ribosome. We have investigated the molecular mechanisms underlying macrolide resistance in Mycobacterium smegmatis, an eubacterium carrying two rRNA operons. Surprisingly, drug resistance was associated not with alterations in ribosomal proteins, but with a single point mutation in the peptidyltransferase region of one of the two 23S RNA genes, i.e. A2058-->G or A2059-->G. This mutation resulted in a heterozygous organism with a mutated and a wild-type rRNA operon respectively. Reverse transcriptase sequencing indicated the expression of both wild-type and mutated rRNAs. The mutated operon was introduced into genetically engineered rrn- strains of M. smegmatis carrying a single functional rRNA operon and into parental M. smegmatis with two chromosomal rRNA operons, using gene transfer as well as gene replacement techniques. The results obtained demonstrate the dominant nature of resistance. As exemplified in our results on macrolide resistance, a complete set of genetic tools is now available, which allows questions of dominance vs. recessivity and gene dosage effects in eubacterial ribosomal nucleic acids to be addressed experimentally in vivo.
Mol Microbiol 1997 Nov
PMID:The role of ribosomal RNAs in macrolide resistance. 940 18

A detailed kinetic study was carried out on the inhibitory mechanisms of two eukaryotic peptidyltransferase drugs (I), anisomycin and sparsomycin. In an in vitro system from rabbit reticulocytes, AcPhe-puromycin is produced in a pseudo-first-order reaction from the preformed AcPhe-tRNA/poly(U)/80S ribosome complex (complex C) and excess puromycin (S). This reaction is inhibited by anisomycin and sparsomycin through different mechanisms. Anisomycin acts as a mixed noncompetitive inhibitor. The product, AcPhe-puromycin, is derived only from C according to the puromycin reaction. On the other hand, sparsomycin reacts with complex C in a two-step reaction, [REACTION; SEE TEXT] An initial rapid binding of the drug produces the encounter complex CI. During this step and before conversion of CI to C*I, sparsomycin behaves as a competitive inhibitor. The rapidly produced CI is isomerized slowly to a conformationally altered species C*I in which I is bound more tightly. The rate constants of this step are k6 = 2.1 min-1 and k7 = 0.095 min-1. Moreover, the low value of the association rate constant k7/Ki' (2 x 10(5) M-1 sec-1), provides insight into the rates of possible conformational changes occurring during protein synthesis and supports the proposal that sparsomycin is the first example of a slow-binding inhibitor of eukaryotic peptidyltransferase. When complex C is preincubated with concentrations of sparsomycin of >8 Ki and then reacts with a mixture of puromycin and sparsomycin, the inhibition becomes linear mixed noncompetitive and involves C*I instead of CI. During this phase, AcPhe-puromycin is produced from a new, modified ribosomal complex with a lower catalytic rate constant. Thus, sparsomycin also acts as a modifier of eukaryotic peptidyltransferase activity.
Mol Pharmacol 1998 Jun
PMID:Kinetics of inhibition of rabbit reticulocyte peptidyltransferase by anisomycin and sparsomycin. 961 13

Cryo-electron microscopy of the ribosome in different binding states with mRNA and tRNA helps unravel the different steps of protein synthesis. Using over 29,000 projections of a ribosome complex in single-particle form, a three-dimensional map of the Escherichia coli 70 S ribosome was obtained in which a single site, the P site, is occupied by fMet-tRNAfMet as directed by an AUG codon containing mRNA. The superior resolution of this three-dimensional map, 14.9 A, has made it possible to fit the tRNA X-ray crystal structure directly and unambiguously into the electron density, thus determining the locations of anticodon-codon interaction and peptidyltransferase center of the ribosome. Furthermore, at this resolution, one of the distinctly visible domains corresponding to a ribosomal protein, L1, closely matches with its X-ray structure.
J Mol Biol 1998 Jul 03
PMID:Escherichia coli 70 S ribosome at 15 A resolution by cryo-electron microscopy: localization of fMet-tRNAfMet and fitting of L1 protein. 965 34


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