Bock, Lars V.

[["dc.bibliographiccitation.artnumber","1709"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Bock, Lars V."],["dc.contributor.author","Grubmüller, Helmut"],["dc.date.accessioned","2022-05-02T08:02:06Z"],["dc.date.available","2022-05-02T08:02:06Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract Structure determination by cryo electron microscopy (cryo-EM) provides information on structural heterogeneity and ensembles at atomic resolution. To obtain cryo-EM images of macromolecules, the samples are first rapidly cooled down to cryogenic temperatures. To what extent the structural ensemble is perturbed during cooling is currently unknown. Here, to quantify the effects of cooling, we combined continuum model calculations of the temperature drop, molecular dynamics simulations of a ribosome complex before and during cooling with kinetic models. Our results suggest that three effects markedly contribute to the narrowing of the structural ensembles: thermal contraction, reduced thermal motion within local potential wells, and the equilibration into lower free-energy conformations by overcoming separating free-energy barriers. During cooling, barrier heights below 10 kJ/mol were found to be overcome, which is expected to reduce B-factors in ensembles imaged by cryo-EM. Our approach now enables the quantification of the heterogeneity of room-temperature ensembles from cryo-EM structures."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft"],["dc.identifier.doi","10.1038/s41467-022-29332-2"],["dc.identifier.pii","29332"],["dc.identifier.pmid","35361752"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/107232"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/503"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-561"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","2041-1723"],["dc.relation.workinggroup","RG Grubmüller"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Effects of cryo-EM cooling on structural ensembles"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2258"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Nucleic Acids Research"],["dc.bibliographiccitation.lastpage","2269"],["dc.bibliographiccitation.volume","50"],["dc.contributor.author","Kolář, Michal H."],["dc.contributor.author","Nagy, Gabor"],["dc.contributor.author","Kunkel, John"],["dc.contributor.author","Vaiana, Sara M."],["dc.contributor.author","Bock, Lars V."],["dc.contributor.author","Grubmüller, Helmut"],["dc.date.accessioned","2022-04-01T10:02:53Z"],["dc.date.available","2022-04-01T10:02:53Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract The ribosome is a fundamental biomolecular complex that synthesizes proteins in cells. Nascent proteins emerge from the ribosome through a tunnel, where they may interact with the tunnel walls or small molecules such as antibiotics. These interactions can cause translational arrest with notable physiological consequences. Here, we studied the arrest caused by the regulatory peptide VemP, which is known to form α-helices inside the ribosome tunnel near the peptidyl transferase center under specific conditions. We used all-atom molecular dynamics simulations of the entire ribosome and circular dichroism spectroscopy to study the driving forces of helix formation and how VemP causes the translational arrest. To that aim, we compared VemP dynamics in the ribosome tunnel with its dynamics in solution. We show that the VemP peptide has a low helical propensity in water and that the propensity is higher in mixtures of water and trifluorethanol. We propose that helix formation within the ribosome is driven by the interactions of VemP with the tunnel and that a part of VemP acts as an anchor. This anchor might slow down VemP progression through the tunnel enabling α-helix formation, which causes the elongation arrest."],["dc.identifier.doi","10.1093/nar/gkac038"],["dc.identifier.pmid","35150281"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/106030"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/502"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-530"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1362-4962"],["dc.relation.issn","0305-1048"],["dc.relation.workinggroup","RG Grubmüller"],["dc.rights","CC BY 4.0"],["dc.title","Folding of VemP into translation-arresting secondary structure is driven by the ribosome exit tunnel"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4466"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Beckert, Bertrand"],["dc.contributor.author","Leroy, Elodie C."],["dc.contributor.author","Sothiselvam, Shanmugapriya"],["dc.contributor.author","Bock, Lars V."],["dc.contributor.author","Svetlov, Maxim S."],["dc.contributor.author","Graf, Michael"],["dc.contributor.author","Arenz, Stefan"],["dc.contributor.author","Abdelshahid, Maha"],["dc.contributor.author","Seip, Britta"],["dc.contributor.author","Grubmüller, Helmut"],["dc.contributor.author","Mankin, Alexander S."],["dc.contributor.author","Innis, C. Axel"],["dc.contributor.author","Vázquez-Laslop, Nora"],["dc.contributor.author","Wilson, Daniel N."],["dc.date.accessioned","2022-02-22T15:58:02Z"],["dc.date.available","2022-02-22T15:58:02Z"],["dc.date.issued","2021"],["dc.description.abstract","Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics."],["dc.identifier.doi","10.1038/s41467-021-24674-9"],["dc.identifier.pmid","34294725"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/100197"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/415"],["dc.language.iso","en"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.issn","2041-1723"],["dc.relation.orgunit","Max-Planck-Institut für biophysikalische Chemie"],["dc.relation.workinggroup","RG Grubmüller"],["dc.rights","CC BY 4.0"],["dc.title","Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]