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)

Sparsomycin is a universal and powerful inhibitor of peptide bond formation which, in contrast to many other ribosome-targeted antibiotics, does not produce footprints on rRNA. A mutant of an archaeon Halobacterium halobium has been isolated that exhibits resistance to sparsomycin. Resistant cells possessed a mutation in the 23 S rRNA, where C2518 (C2499 in Escherichia coli) was substituted by U. Introduction of the C2518U mutation into the chromosomal 23 S rRNA gene of wild-type H. halobium rendered cells resistant to sparsomycin, demonstrating that a single nucleotide alteration in the rRNA is sufficient to confer resistance. Accordingly, ribosomes containing mutant 23 S rRNA exhibited increased tolerance to sparsomycin in vitro. Mutations of two other nucleotide positions in the peptidyl transferase center, C2471 and U2519 (C2452 and U2500 in E. coli), conferred resistance to low concentrations of sparsomycin. The location of the sparsomycin resistance mutations reveals the possible site of drug binding and/or action. Our findings provide further support for the idea that rRNA may be directly involved in interaction with antibiotics and the catalysis of the peptide bond formation.
J Mol Biol 1996 Aug 16
PMID:Mutations in the peptidyl transferase center of 23 S rRNA reveal the site of action of sparsomycin, a universal inhibitor of translation. 875 89

Sparsomycin, a broad-spectrum antibiotic, acts at the peptidyl transferase centre of the ribosome, stabilizing peptidyl-tRNA binding at the P-site and weakening ternary complex binding. A sparsomycin-resistant mutant was isolated for the archaeon Halobacterium salinarium and shown to lack a post-transcriptional modification of U2603 (Escherichia coli numbering U2584), which is a universally conserved uridine base located within the peptidyl transferase loop of 23 S rRNA. This mutant also exhibited altered sensitivities to the peptidyl transferase antibiotics anisomycin, chloramphenicol and puromycin. Several lines of evidence indicate that the unmodified uridine base lies within the P-substrate site of the peptidyl transferase centre.
J Mol Biol 1996 Aug 16
PMID:A sparsomycin-resistant mutant of Halobacterium salinarium lacks a modification at nucleotide U2603 in the peptidyl transferase centre of 23 S rRNA. 875 90

Crystal structures of tRNA mimics complexed with the large ribosomal subunit of Deinococcus radiodurans indicate that remote interactions determine the precise orientation of tRNA in the peptidyl-transferase center (PTC). The PTC tolerates various orientations of puromycin derivatives and its flexibility allows the conformational rearrangements required for peptide-bond formation. Sparsomycin binds to A2602 and alters the PTC conformation. H69, the intersubunit-bridge connecting the PTC and decoding site, may also participate in tRNA placement and translocation. A spiral rotation of the 3' end of the A-site tRNA around a 2-fold axis of symmetry identified within the PTC suggests a unified ribosomal machinery for peptide-bond formation, A-to-P-site translocation, and entrance of nascent proteins into the exit tunnel. Similar 2-fold related regions, detected in all known structures of large ribosomal subunits, indicate the universality of this mechanism.
Mol Cell 2003 Jan
PMID:Structural basis of the ribosomal machinery for peptide bond formation, translocation, and nascent chain progression. 1253 24

Structures of anisomycin, chloramphenicol, sparsomycin, blasticidin S, and virginiamycin M bound to the large ribosomal subunit of Haloarcula marismortui have been determined at 3.0A resolution. Most of these antibiotics bind to sites that overlap those of either peptidyl-tRNA or aminoacyl-tRNA, consistent with their functioning as competitive inhibitors of peptide bond formation. Two hydrophobic crevices, one at the peptidyl transferase center and the other at the entrance to the peptide exit tunnel play roles in binding these antibiotics. Midway between these crevices, nucleotide A2103 of H.marismortui (2062 Escherichia coli) varies in its conformation and thereby contacts antibiotics bound at either crevice. The aromatic ring of anisomycin binds to the active-site hydrophobic crevice, as does the aromatic ring of puromycin, while the aromatic ring of chloramphenicol binds to the exit tunnel hydrophobic crevice. Sparsomycin contacts primarily a P-site bound substrate, but also extends into the active-site hydrophobic crevice. Virginiamycin M occupies portions of both the A and P-site, and induces a conformational change in the ribosome. Blasticidin S base-pairs with the P-loop and thereby mimics C74 and C75 of a P-site bound tRNA.
J Mol Biol 2003 Jul 25
PMID:Structures of five antibiotics bound at the peptidyl transferase center of the large ribosomal subunit. 1286 Jan 28