Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity

Davidovich, Chen; Bashan, Anat; Auerbach-Nevo, T.; Yaggie, Rachel D.; Gontarek, Richard R.; Yonath, Ada

doi:10.1073/pnas.0700041104

Cited by 180 publications

(185 citation statements)

References 53 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…In the SA50S-BC3205 crystal structure, BC-3205 is bound at the PTC, so that the tricyclic mutilin core is blocking the A-site, and its C14 extension is pointing into the P-site, thus perturbing A-and P-site tRNA accommodation, as was seen in the ribosome-pleuromutilin complexes with D50S (35,36). In the SA50S-BC3205 complex, the conformation of the flexible nucleotide U2585 is different from that of the unbound SA50S, and its conformational range is reduced because of partial overlap by the BC-3205 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In all cases, their cores are placed in a similar fashion at the A-site and their C14 extensions are pointing toward the P-site; thus, they directly inhibit peptide bond formation. Because the PTC is almost fully conserved, the clinical efficacy of the pleuromutilins stems from their efficient inhibitory modes, which are attained by structural diversity in the second or third shells around the PTC, by exploiting the ribosomal intrinsic functional flexibility for induced fit and remote conformational rearrangements that result in a tightening up of the binding pockets (35,36).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus

Eyal

Matzov

Krupkin

et al. 2015

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

Self Cite

121

151

View full text Add to dashboard Cite

The emergence of bacterial multidrug resistance to antibiotics threatens to cause regression to the preantibiotic era. Here we present the crystal structure of the large ribosomal subunit from Staphylococcus aureus, a versatile Gram-positive aggressive pathogen, and its complexes with the known antibiotics linezolid and telithromycin, as well as with a new, highly potent pleuromutilin derivative, BC-3205. These crystal structures shed light on specific structural motifs of the S. aureus ribosome and the binding modes of the aforementioned antibiotics. Moreover, by analyzing the ribosome structure and comparing it with those of nonpathogenic bacterial models, we identified some unique internal and peripheral structural motifs that may be potential candidates for improving known antibiotics and for use in the design of selective antibiotic drugs against S. aureus.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus

Eyal

Matzov

Krupkin

et al. 2015

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

Self Cite

121

151

View full text Add to dashboard Cite

show abstract

“…Additionally, similar to pleuromutilins that utilize a network of remote interactions, LC binding is influenced by the second-shell nucleotides, specifically G2576, A2062, C2530, U2531, C2507, U2584, G2581, C2610, and A2059. Thus, LC exploits the PTC's inherent flexibility for achieving high binding affinity (9,10).…”

Section: Resultsmentioning

confidence: 99%

“…Crystallographic studies performed over the last decade revealed the exact binding sites of a variety of such drugs (see refs.1 and 2 for review). Many natural antibiotics, as well as their clinically relevant semisynthetic derivatives, bind at the peptidyl transferase center (PTC) in the large ribosomal subunit (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Most of these compounds inhibit cell growth by interfering with peptide bond formation (15).…”

mentioning

confidence: 99%

The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics

Auerbach

Mermershtain

Davidovich

et al. 2010

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

Self Cite

View full text Add to dashboard Cite

Crystallographic analysis revealed that the 17-member polyketide antibiotic lankacidin produced by Streptomyces rochei binds at the peptidyl transferase center of the eubacterial large ribosomal subunit. Biochemical and functional studies verified this finding and showed interference with peptide bond formation. Chemical probing indicated that the macrolide lankamycin, a second antibiotic produced by the same species, binds at a neighboring site, at the ribosome exit tunnel. These two antibiotics can bind to the ribosome simultaneously and display synergy in inhibiting bacterial growth. The binding site of lankacidin and lankamycin partially overlap with the binding site of another pair of synergistic antibiotics, the streptogramins. Thus, at least two pairs of structurally dissimilar compounds have been selected in the course of evolution to act synergistically by targeting neighboring sites in the ribosome. These results underscore the importance of the corresponding ribosomal sites for development of clinically relevant synergistic antibiotics and demonstrate the utility of structural analysis for providing new directions for drug discovery.lankamycin | ribosomes | synergism | resistance | rRNA

show abstract

“…On the other hand, the same binding pockets may accommodate chemically different antibiotics. Similarly, the nature of seemingly identical mechanisms of drug resistance is dominated, directly or via cellular effects, by the antibiotics' chemical properties (Davidovich et al 2007. The observed variability in antibioticbinding and inhibitory modes justifies expectations for structurally based improved properties of existing compounds as well as for the discovery of novel drug classes.…”

Section: From In-house X-ray Generators To Advanced Synchrotron Radiamentioning

confidence: 99%

Large facilities and the evolving ribosome, the cellular machine for genetic-code translation

Yonath

2009

J. R. Soc. Interface.

Self Cite

View full text Add to dashboard Cite

Well-focused X-ray beams, generated by advanced synchrotron radiation facilities, yielded high-resolution diffraction data from crystals of ribosomes, the cellular nano-machines that translate the genetic code into proteins. These structures revealed the decoding mechanism, localized the mRNA path and the positions of the tRNA molecules in the ribosome and illuminated the interactions of the ribosome with initiation, release and recycling factors. They also showed that the ribosome is a ribozyme whose active site is situated within a universal symmetrical region that is embedded in the otherwise asymmetric ribosome structure. As this highly conserved region provides the machinery required for peptide bond formation and for ribosome polymerase activity, it may be the remnant of the proto-ribosome, a dimeric prebiotic machine that formed peptide bonds and non-coded polypeptide chains. Synchrotron radiation also enabled the determination of structures of complexes of ribosomes with antibiotics targeting them, which revealed the principles allowing for their clinical use, revealed resistance mechanisms and showed the bases for discriminating pathogens from hosts, hence providing valuable structural information for antibiotics improvement.

show abstract

Induced-fit tightens pleuromutilins binding to ribosomes and remote interactions enable their selectivity

Abstract: antibiotics ͉ functional flexibility ͉ ribosome crystallography ͉ peptidyl transferase center ͉ retapamulin

Cited by 180 publications

References 53 publications

Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus

Structural insights into species-specific features of the ribosome from the pathogen Staphylococcus aureus

The structure of ribosome-lankacidin complex reveals ribosomal sites for synergistic antibiotics

Large facilities and the evolving ribosome, the cellular machine for genetic-code translation

Contact Info

Product

Resources

About