scholarly journals Interaction of Pleuromutilin Derivatives with the Ribosomal Peptidyl Transferase Center

2006 ◽  
Vol 50 (4) ◽  
pp. 1458-1462 ◽  
Author(s):  
Katherine S. Long ◽  
Lykke H. Hansen ◽  
Lene Jakobsen ◽  
Birte Vester
Keyword(s):  
Drug Targets ◽  
Rational Design ◽  
Ribosomal Subunit ◽  
Binding Pocket ◽  
Chain Extension ◽  
Side Chain ◽  
Peptidyl Transferase ◽  
Peptidyl Transferase Center ◽  
Binding Surface ◽  
The Common

ABSTRACT Tiamulin is a pleuromutilin antibiotic that is used in veterinary medicine. The recently published crystal structure of a tiamulin-50S ribosomal subunit complex provides detailed information about how this drug targets the peptidyl transferase center of the ribosome. To promote rational design of pleuromutilin-based drugs, the binding of the antibiotic pleuromutilin and three semisynthetic derivatives with different side chain extensions has been investigated using chemical footprinting. The nucleotides A2058, A2059, G2505, and U2506 are affected in all of the footprints, suggesting that the drugs are similarly anchored in the binding pocket by the common tricyclic mutilin core. However, varying effects are observed at U2584 and U2585, indicating that the side chain extensions adopt distinct conformations within the cavity and thereby affect the rRNA conformation differently. An Escherichia coli L3 mutant strain is resistant to tiamulin and pleuromutilin, but not valnemulin, implying that valnemulin is better able to withstand an altered rRNA binding surface around the mutilin core. This is likely due to additional interactions made between the valnemulin side chain extension and the rRNA binding site. The data suggest that pleuromutilin drugs with enhanced antimicrobial activity may be obtained by maximizing the number of interactions between the side chain moiety and the peptidyl transferase cavity.

scholarly journals Association of snR190 snoRNA chaperone with early pre-60S particles is regulated by the RNA helicase Dbp7 in yeast

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mariam Jaafar ◽  
Julia Contreras ◽  
Carine Dominique ◽  
Sara Martín-Villanueva ◽  
Régine Capeyrou ◽  
...  
Keyword(s):  
Ribosomal Rna ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Rna Helicase ◽  
Genetic Interactions ◽  
Large Ribosomal Subunit ◽  
Base Pairing ◽  
Peptidyl Transferase ◽  
Peptidyl Transferase Center

AbstractSynthesis of eukaryotic ribosomes involves the assembly and maturation of precursor particles (pre-ribosomal particles) containing ribosomal RNA (rRNA) precursors, ribosomal proteins (RPs) and a plethora of assembly factors (AFs). Formation of the earliest precursors of the 60S ribosomal subunit (pre-60S r-particle) is among the least understood stages of ribosome biogenesis. It involves the Npa1 complex, a protein module suggested to play a key role in the early structuring of the pre-rRNA. Npa1 displays genetic interactions with the DExD-box protein Dbp7 and interacts physically with the snR190 box C/D snoRNA. We show here that snR190 functions as a snoRNA chaperone, which likely cooperates with the Npa1 complex to initiate compaction of the pre-rRNA in early pre-60S r-particles. We further show that Dbp7 regulates the dynamic base-pairing between snR190 and the pre-rRNA within the earliest pre-60S r-particles, thereby participating in structuring the peptidyl transferase center (PTC) of the large ribosomal subunit.

scholarly journals Cryo-EM structure of the B cell co-receptor CD19 bound to the tetraspanin CD81

Science ◽  
2021 ◽  
Vol 371 (6526) ◽  
pp. 300-305
Author(s):  
Katherine J. Susa ◽  
Shaun Rawson ◽  
Andrew C. Kruse ◽  
Stephen C. Blacklow
Keyword(s):  
B Cell ◽  
Rational Design ◽  
Cell Receptor ◽  
Binding Pocket ◽  
Structural Basis ◽  
Transmembrane Helices ◽  
Critical Determinant ◽  
Cell Dysfunction ◽  
Cryo Electron Microscopy ◽  
Binding Surface

Signaling through the CD19-CD81 co-receptor complex, in combination with the B cell receptor, is a critical determinant of B cell development and activation. It is unknown how CD81 engages CD19 to enable co-receptor function. Here, we report a 3.8-angstrom structure of the CD19-CD81 complex bound to a therapeutic antigen-binding fragment, determined by cryo–electron microscopy (cryo-EM). The structure includes both the extracellular domains and the transmembrane helices of the complex, revealing a contact interface between the ectodomains that drives complex formation. Upon binding to CD19, CD81 opens its ectodomain to expose a hydrophobic CD19-binding surface and reorganizes its transmembrane helices to occlude a cholesterol binding pocket present in the apoprotein. Our data reveal the structural basis for CD19-CD81 complex assembly, providing a foundation for rational design of therapies for B cell dysfunction.

scholarly journals Tightly-orchestrated rearrangements govern catalytic center assembly of the ribosome

2018 ◽  
Author(s):  
Yi Zhou ◽  
Sharmishtha Musalgaonkar ◽  
Arlen W. Johnson ◽  
David W. Taylor
Keyword(s):  
Catalytic Activity ◽  
Large Subunit ◽  
Ribosomal Subunit ◽  
Critical Element ◽  
Large Ribosomal Subunit ◽  
Peptidyl Transferase ◽  
Catalytic Center ◽  
Peptidyl Transferase Center ◽  
Final Assembly ◽  
Cytoplasmic Maturation

AbstractThe catalytic activity of the ribosome is mediated by RNA, yet proteins are essential for the function of the peptidyl transferase center (PTC). In eukaryotes, final assembly of the PTC occurs in the cytoplasm by insertion of the ribosomal protein Rpl10. We determine structures of six intermediates in late nuclear and cytoplasmic maturation of the large subunit that reveal a tightly-choreographed sequence of protein and RNA rearrangements controlling the insertion of Rpl10. We also determine the structure of the biogenesis factor Yvh1 and show how it promotes assembly of the P stalk, a critical element for recruitment of GTPases that drive translation. Together, our structures provide a blueprint for final assembly of a functional ribosome.One Sentence SummaryCryo-EM structures of six novel intermediates in the assembly of the large ribosomal subunit reveal mechanism of creating the catalytic center.

scholarly journals Induced-fit of the peptidyl-transferase center of the ribosome and conformational freedom of the esterified amino acids

2015 ◽  
Author(s):  
Jean Lehmann
Keyword(s):  
Amino Acids ◽  
Similar Rate ◽  
Catalytic Site ◽  
Side Chain ◽  
Peptidyl Transferase ◽  
Induced Fit ◽  
Independent Manner ◽  
Peptidyl Transferase Center ◽  
Conformational Freedom ◽  
A Site

The catalytic site of most enzymes can essentially deal with only one substrate. In contrast, the ribosome is capable of polymerizing at a similar rate at least 20 different kinds of amino acids from aminoacyl-tRNA carriers while using just one catalytic site, the peptidyl-transferase center (PTC). An induced-fit mechanism has been uncovered in the PTC, but a possible connection between this mechanism and the uniform handling of the substrates has not been investigated. We present an analysis of published ribosome structures supporting the hypothesis that the induced-fit eliminates unreactive rotamers predominantly populated for some A-site aminoacyl esters before induction. We show that this hypothesis is fully consistent with the wealth of kinetic data obtained with these substrates. Our analysis reveals that induction constrains the amino acids into a reactive conformation in a side-chain independent manner. It allows us to highlight the rationale of the PTC structural organization, which confers to the ribosome the very unusual ability to handle large as well as small substrates.

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