Interaction of antibiotics with functional sites in 16S ribosomal RNA

Moazed, Danesh; Noller, Harry F.

doi:10.1038/327389a0

Cited by 1,114 publications

(895 citation statements)

References 39 publications

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“…In addition to ARFP, our sequence analysis also suggests the presence of RNA structural elements, at least some of which may modulate expression of HCV proteins+ Within the core-encoding region we find sequence conservation that extends beyond the ARFP, indicating the potential presence of RNA regulatory elements+ Interactions between RNA sequences in the 59 nontranslated region and those in the core-encoding region have recently been reported by Honda and colleagues, and are associated with alterations in the efficiency of protein translation (Honda et al+, 1999)+ One RNA element detected in our analysis that had not been described previously is located near the carboxyl terminus of E2 (see Fig+ 2, cluster 2)+ We also found evidence of RNA elements in the NS5b-encoding regions (see Fig+ 2, clusters 3, 4, and 5), in keeping with observations by Smith and Simmonds (1997)+ These elements, alone or in combination with RNA elements elsewhere in the genome, could function in HCV replication, virion assembly or translation modulation+ Whatever their function, once the structures of these elements are known, they will become potential targets for RNA-binding pharmaceutical agents, similar to the aminoglycoside antibiotics, which interact with intricate three-dimensional RNA structures in (bacterial) ribosomal RNA (Moazed & Noller, 1987)+…”

Section: Other Cryptic Elements In Hcv Rnamentioning

confidence: 68%

Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame

Walewski

Keller

Stump

et al. 2001

RNA

240

227

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Many viruses have overlapping genes and/or regions in which a nucleic acid signal is embedded in a coding sequence. To search for dual-use regions in the hepatitis C virus (HCV), we developed a facile computer-based sequence analysis method to map dual-use regions in coding sequences. Eight diverse full-length HCV RNA and polyprotein sequences were aligned and analyzed. A cluster of unusually conserved synonymous codons was found in the core-encoding region, indicating a potential overlapping open reading frame (ORF). Four peptides (A1, A2, A3, and A4) representing this alternate reading frame protein (ARFP), two others from the HCV core protein, and one from bovine serum albumin (BSA) were conjugated to BSA and used in western blots to test sera for specific antibodies from 100 chronic HCV patients, 44 healthy controls, and 60 patients with non-HCV liver disease. At a 1:20,000 dilution, specific IgGs to three of the four ARFP peptides were detected in chronic HCV sera. Reactivity to either the A1 or A3 peptides (both ARFP derived) was significantly associated with chronic HCV infection, when compared to non-HCV liver disease serum samples (10/100 versus 1/60; p , 0.025). Antibodies to A4 were not detected in any serum sample. Our western blot assays confirmed the presence of specific antibodies to a new HCV antigen encoded, at least in part, in an alternate reading frame (ARF) overlapping the core-encoding region. Because this novel HCV protein stimulates specific immune responses, it has potential value in diagnostic tests and as a component of vaccines. This protein is predicted to be highly basic and may play a role in HCV replication, pathogenesis, and carcinogenesis.

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Section: Other Cryptic Elements In Hcv Rnamentioning

confidence: 68%

Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame

Walewski

Keller

Stump

et al. 2001

RNA

240

227

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“…They all are bisubstrate enzymes that transfer functional groups from one of their substrates to the aminoglycoside, thus compromising the binding of the modified drug to its target, the bacterial ribosome. 8 Aminoglycoside acetyltransferases (AACs) use acetyl-coA as the second substrate to acetylate the 1, 3, 2 0 , or 6 0 amino groups of these antibiotics (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Crystal structure and kinetic mechanism of aminoglycoside phosphotransferase‐2″‐IVa

et al. 2010

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Acquired resistance to aminoglycoside antibiotics primarily results from deactivation by three families of aminoglycoside-modifying enzymes. Here, we report the kinetic mechanism and structure of the aminoglycoside phosphotransferase 2 00 -IVa (APH(2 00 )-IVa), an enzyme responsible for resistance to aminoglycoside antibiotics in clinical enterococcal and staphylococcal isolates. The enzyme operates via a Bi-Bi sequential mechanism in which the two substrates (ATP or GTP and an aminoglycoside) bind in a random manner. The APH(2 00 )-IVa enzyme phosphorylates various 4,6-disubstituted aminoglycoside antibiotics with catalytic efficiencies (k cat /K m ) of 1.5 3 10 3 to 1.2 3 10 6 (M 21 s 21 ). The enzyme uses both ATP and GTP as the phosphate source, an extremely rare occurrence in the phosphotransferase and protein kinase enzymes. Based on an analysis of the APH(2 00 )-IVa structure, two overlapping binding templates specifically tuned for hydrogen bonding to either ATP or GTP have been identified and described. A detailed understanding of the structure and mechanism of the GTP-utilizing phosphotransferases is crucial for the development of either novel aminoglycosides or, more importantly, GTP-based enzyme inhibitors which would not be expected to interfere with crucial ATP-dependent enzymes.

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“…Aminoglycoside antibiotics, quinoxaline-2,3-diones, and 2,4-diaminoquinozalines have been found to be potent inhibitors. Among them, aminoglycoside antibiotics have previously been reported (20) to exert their antibacterial functions by interacting with the decoding region of ribosomal RNA. There has been significant interest in understanding the details of how these antibiotics interact with various RNA targets (21).…”

Section: Identification Of Three Small Molecule Tat-tar Inhibitorsmentioning

confidence: 99%

Inhibitors of Protein−RNA Complexation That Target the RNA: Specific Recognition of Human Immunodeficiency Virus Type 1 TAR RNA by Small Organic Molecules

Mei¹,

Cui²,

Heldsinger³

et al. 1998

Biochemistry

158

140

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TAR RNA represents an attractive target for the intervention of human immunodeficiency virus type 1 (HIV-1) replication by small molecules. We now describe three small molecule inhibitors of the HIV-1 Tat-TAR interaction that target the RNA, not the protein. The chemical structures and RNA binding characteristics of these inhibitors are unique for each molecule. Results from various biochemical and spectroscopic methods reveal that each of the three Tat-TAR inhibitors recognizes a different structural feature at the bulge, lower stem, or loop region of TAR. Furthermore, one of these Tat-TAR inhibitors has been demonstrated, in cellular environments, to inhibit (a) a TAR-dependent, Tat-activated transcription and (b) the replication of HIV-1 in a latently infectious model. Drug discovery has traditionally involved a search for inhibitors of protein complexation to small molecules (e.g., substrates or ligands) or macromolecules (e.g., other proteins, nucleic acids, or polysaccharides). While agonists or antagonists of macromolecular receptors that become useful drugs must display a wide range of other attributes, including the appropriate physicochemical properties, pharmacokinetic and pharmacodynamic properties, stability, etc., they must first be protein ligands. The vast majority of available drugs act by binding noncovalently to a protein, preventing or (less often) stimulating that protein's complexation to a complement (1).Complexes of nucleic acid and proteins are key intermediates in all transcriptional and translational processes. Some nucleic acids (e.g., ribozymes) even form functional complexes with small molecules (2). Nonetheless, nucleic acids are widely viewed as ineffective targets for the discovery of low-molecular weight inhibitors. One reason is that the linear motif in single-stranded DNA and the repetitive motif in double-stranded DNA provide attractive targets for large, linear binding molecules (3), but unattractive targets for the small molecules that lead to orally available medications. Another reason is that the lack of tertiary structure in DNA does not afford the diverse topology associated with folded proteins.However, single-stranded RNA often folds into welldefined tertiary structures (4). Furthermore, such structures serve as docking sites for transcriptional activators (5) and substrates for self-splicing reactions (6, 7). Can such structured nucleic acids display sufficient shape diversity to permit the complexation of a small molecule at one site in a virtual sea of nucleic acid material? This is the essential question whose presumed negative answer hinders drug discovery at the nucleic acid level.Certain cis-acting RNA elements are essential for the gene expression of human immunodeficiency virus type 1 (HIV-1) (8). The functions and sequences of these RNA molecules have been well characterized (9-11). A segment of HIV-1 mRNA (residues 1-59), identified as the transactivation responsive element (TAR), adopts a stem-loop secondary structure consisting of a highly cons...

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Interaction of antibiotics with functional sites in 16S ribosomal RNA

Cited by 1,114 publications

References 39 publications

Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame

Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame

Crystal structure and kinetic mechanism of aminoglycoside phosphotransferase‐2″‐IVa

Inhibitors of Protein−RNA Complexation That Target the RNA: Specific Recognition of Human Immunodeficiency Virus Type 1 TAR RNA by Small Organic Molecules

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