Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin

Harms, Joerg; Schlünzen, Frank; Fucini, Paola; Bartels, Heike; Yonath, Ada

doi:10.1186/1741-7007-2-4

Cited by 156 publications

(108 citation statements)

References 52 publications

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“…This non-productive U2585 conformation, can, in turn, be stabilized by the binding of quinupristin, the second Synercid 1 component, thus leading to a prominent synergetic effect. 14 We conclude, therefore, that the PTC interference with D-aa incorporation into a growing chain is based on space considerations as well as on the creation of unproductive interactions, which could be irreversible. Substantial conformational rearrangements within the PTC could bypass both mechanisms, consistent with the suggestion based on mutation experiments.…”

Section: Controlling the Elimination Of D-amino Acidsmentioning

confidence: 99%

“…erythromycin) hydrogen bonds. 12 Similar to other macrolides, [12][13][14][15][16]62 TAO binds to the exit tunnel, close to its entrance. 15 It exploits the macrolide favorable binding site, namely the vicinity of A2058, in a rather unique fashion [Plate 3(a)], presumably dictated by its size and chemical properties.…”

Section: Tunnel Discrimination Of Nascent Proteinsmentioning

confidence: 99%

“…Nevertheless, the crystal structures of more than a dozen complexes of antibiotics bound to the large subunit from Deinococcus radiodurans, a eubacterium proved to be suitable to serve as a pathogen model for ribosomal antibiotics, show that practically all of the known drugs utilize a single or very few binding sites. [12][13][14][15][16] The findings presented in this review are based mainly on the high-resolution structures of the small ribosomal subunit from Thermus thermophilus T30S 4 [Plate 1(a)] and the large ribosomal subunit from D. radiodurans, D50S, in its free form 7 [Plate 1(b)] as well as in complexes with various mimics of aminoacylated tRNA molecules. 8 Here, we discuss some of the latest advances in the understanding of the molecular basis of the catalytic mechanism of peptide bond formation, and of the ribosomal action as an amino acid polymerase.…”

Section: Introductionmentioning

confidence: 99%

“…Crystallography of ribosomes, initiated over two decades ago 1 recently yielded several three-dimensional structures of free and complexes ribosomal particles [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and enabled the assignments of the three tRNA binding sites on each of the ribosomal subunits to be made [plate 1(a) and (b)]. They also confirmed the notion that the main parts of the A-and P-site tRNA molecules are roughly parallel to each other, whereas the E-site tRNA has to rotate while exiting the ribosome.…”

Section: Introductionmentioning

confidence: 99%

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Functional aspects of ribosomal architecture: symmetry, chirality and regulation

Zarivach

Bashan

Berisio

et al. 2004

J of Physical Organic Chem

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High-resolution structures of both ribosomal subunits revealed that most stages of protein biosynthesis, including decoding of genetic information, are navigated and controlled by the elaborate ribosomal architecturaldesign. Remote interactions govern accurate substrate alignment within a flexible active-site pocket [peptidyl transferase center (PTC)], and spatial considerations, due mainly to a universal mobile nucleotide, U2585, ensure proper chirality by interfering with D-amino-acids incorporation. tRNA translocation involves two correlated motions: overall mRNA/tRNA (messenger and transfer RNA) shift, and a rotation of the tRNA single-stranded aminoacylated-3 0 end around the bond connecting it with the tRNA helical-regions. This bond coincides with an axis passing through a sizable symmetry-related region, identified around the PTC in all large-subunit crystal structures. Propelled by a bulged universal nucleotide, A2602, positioned at the two-fold symmetry axis, and guided by a ribosomal-RNA scaffold along an exact pattern, the rotatory motion results in stereochemistry optimal for peptide-bond formation and in geometry ensuring nascent proteins entrance into their exit tunnel. Hence, confirming that ribosomes contribute positional rather than chemical catalysis, and that peptide bond formation is concurrent with A-to P-site tRNA passage. Connecting between the PTC, the decoding center, the tRNA entrance and exit points, the symmetry-related region can transfer intra-ribosomal signals between remote functional locations, guaranteeing smooth processivity of amino acids polymerization. Ribosomal proteins are involved in accurate substrate placement (L16), discrimination and signal transmission (L22) and protein biosynthesis regulation (CTC). Residing on the exit tunnel walls near its entrance, and stretching to its opening, protein-L22 can mediate ribosome response to cellular regulatory signals, since it can swing across the tunnel, causing gating and elongation arrest. Each of the protein CTC domains has a defined task. The N-terminal domain stabilizes the intersubunit-bridge confining the A-site-tRNA entrance. The middle domain protects the bridge conformation at elevated temperatures. The C-terminal domain can undergo substantial conformational rearrangements upon substrate binding, indicating CTC participation in biosynthesiscontrol under stressful conditions.

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Section: Controlling the Elimination Of D-amino Acidsmentioning

confidence: 99%

Section: Tunnel Discrimination Of Nascent Proteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Functional aspects of ribosomal architecture: symmetry, chirality and regulation

Zarivach

Bashan

Berisio

et al. 2004

J of Physical Organic Chem

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“…These drugs block protein translation by binding to the P-site of the ribosome (type A streptogramin) and by occluding the entrance to the peptide exit tunnel (type B streptogramin). Binding of the type A streptogramin results in a conformational change in the ribosome that facilitates binding of the type B streptogramin (3)(4)(5). It is this inhibitor-induced conformational change that forms the molecular basis of the synergistic antimicrobial activity that is the hallmark of this class of antibiotics.…”

mentioning

confidence: 99%

Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase

Korczynska

Mukhtar

Wright

et al. 2007

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

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The streptogramin combination therapy of quinupristin-dalfopristin (Synercid) is used to treat infections caused by bacterial pathogens, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. However, the effectiveness of this therapy is being compromised because of an increased incidence of streptogramin resistance. One of the clinically observed mechanisms of resistance is enzymatic inactivation of the type B streptogramins, such as quinupristin, by a streptogramin B lyase, i.e., virginiamycin B lyase (Vgb). The enzyme catalyzes the linearization of the cyclic antibiotic via a cleavage that requires a divalent metal ion. Here, we present crystal structures of Vgb from S. aureus in its apoenzyme form and in complex with quinupristin and Mg 2؉ at 1.65-and 2.8-Å resolution, respectively. The fold of the enzyme is that of a seven-bladed ␤-propeller, although the sequence reveals no similarity to other known members of this structural family. Quinupristin binds to a large depression on the surface of the enzyme, where it predominantly forms van der Waals interactions. Validated by site-directed mutagenesis studies, a reaction mechanism is proposed in which the initial abstraction of a proton is facilitated by a Mg 2؉ -linked conjugated system. Analysis of the Vgb-quinupristin structure and comparison with the complex between quinupristin and its natural target, the 50S ribosomal subunit, reveals features that can be exploited for developing streptogramins that are impervious to Vgb-mediated resistance.antibiotic resistance ͉ enzyme mechanism ͉ crystal structure

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Therapeutic Agents Acting on RNA Targets

Rife

2010

Burger's Medicinal Chemistry and Drug Discovery

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There are many therapeutics that target RNA, such as streptomycin, gentamicin, and tetracycline; some of them have been in existence for many years. All of them bind to ribosomal RNA and alter normal ribosome function. The modern strategies of drug discovery and design pertain nearly exclusively to protein targets. However, the field of drug discovery for RNA targets is maturing rapidly, largely due to the exciting ribosome/drug complexes that have recently been solved. Potential RNA drug targets abound for bacterial, viral, and cellular systems. Nevertheless, questions remain as to whether or not compounds can be found that simultaneously satisfy RNA binding and pharmacological properties, such as absorption and membrane permeation. The range of interactions observed, from Coulombic to hydrophobic, and the predicted “drug‐like” qualities of several ribosome binding antibiotics, suggest that the discovery of drugs that target RNA can be a general phenomenon.

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Alterations at the peptidyl transferase centre of the ribosome induced by the synergistic action of the streptogramins dalfopristin and quinupristin

Cited by 156 publications

References 52 publications

Functional aspects of ribosomal architecture: symmetry, chirality and regulation

Functional aspects of ribosomal architecture: symmetry, chirality and regulation

Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase

Therapeutic Agents Acting on RNA Targets

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