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The ribosome termination complex remodels release factor RF3 and ejects GDP. 核糖体终止复合体重塑释放因子 RF3 并排出 GDP。
IF 16.8 1区 生物学
Nature Structural &Molecular Biology Pub Date : 2024-07-19 DOI: 10.1038/s41594-024-01360-0
Li Li, Mariia Yu Rybak, Jinzhong Lin, Matthieu G Gagnon
{"title":"The ribosome termination complex remodels release factor RF3 and ejects GDP.","authors":"Li Li, Mariia Yu Rybak, Jinzhong Lin, Matthieu G Gagnon","doi":"10.1038/s41594-024-01360-0","DOIUrl":"10.1038/s41594-024-01360-0","url":null,"abstract":"<p><p>Translation termination involves release factors RF1, RF2 and the GTPase RF3 that recycles RF1 and RF2 from the ribosome. RF3 dissociates from the ribosome in the GDP-bound form and must then exchange GDP for GTP. The 70S ribosome termination complex (70S-TC) accelerates GDP exchange in RF3, suggesting that the 70S-TC can function as the guanine nucleotide exchange factor for RF3. Here, we use cryogenic-electron microscopy to elucidate the mechanism of GDP dissociation from RF3 catalyzed by the Escherichia coli 70S-TC. The non-rotated ribosome bound to RF1 remodels RF3 and induces a peptide flip in the phosphate-binding loop, efficiently ejecting GDP. Binding of GTP allows RF3 to dock at the GTPase center, promoting the dissociation of RF1 from the ribosome. The structures recapitulate the functional cycle of RF3 on the ribosome and uncover the mechanism by which the 70S-TC allosterically dismantles the phosphate-binding groove in RF3, a previously overlooked function of the ribosome.</p>","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":16.8,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules 帕金森病相关LRRK2与微管结合的结构基础
IF 16.8 1区 生物学
Nature Structural &Molecular Biology Pub Date : 2022-01-22 DOI: 10.1101/2022.01.21.477284
D. Snead, M. Matyszewski, Andrea M. Dickey, Yu Lin, A. Leschziner, Samara L. Reck-Peterson
{"title":"Structural basis for Parkinson’s disease-linked LRRK2’s binding to microtubules","authors":"D. Snead, M. Matyszewski, Andrea M. Dickey, Yu Lin, A. Leschziner, Samara L. Reck-Peterson","doi":"10.1101/2022.01.21.477284","DOIUrl":"https://doi.org/10.1101/2022.01.21.477284","url":null,"abstract":"Leucine Rich Repeat Kinase 2 (LRRK2) is one of the most commonly mutated genes in familial Parkinson’s Disease (PD). Under some circumstances, LRRK2 co-localizes with microtubules in cells, an association enhanced by PD mutations. We report a cryo-electron microscopy structure of the catalytic half of LRRK2, containing its kinase, which is in a closed conformation, and GTPase domains, bound to microtubules. We also report a structure of the catalytic half of LRRK1, which is closely related to LRRK2, but is not linked to PD. LRRK1’s structure is similar to LRRK2, but LRRK1 does not interact with microtubules. Guided by these structures, we identify amino acids in LRRK2’s GTPase domain that mediate microtubule binding; mutating them disrupts microtubule binding in vitro and in cells, without affecting LRRK2’s kinase activity. Our results have implications for the design of therapeutic LRRK2 kinase inhibitors.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"29 1","pages":"1196 - 1207"},"PeriodicalIF":16.8,"publicationDate":"2022-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41446644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 11
Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics 恶唑烷酮类抗生素对翻译特异性抑制的结构基础
IF 16.8 1区 生物学
Nature Structural &Molecular Biology Pub Date : 2021-08-10 DOI: 10.1101/2021.08.10.455846
K. Tsai, Vanja Stojković, D. J. Lee, Iris D. Young, Teresa Szal, N. Vázquez-Laslop, A. Mankin, James S. Fraser, D. Fujimori
{"title":"Structural basis for context-specific inhibition of translation by oxazolidinone antibiotics","authors":"K. Tsai, Vanja Stojković, D. J. Lee, Iris D. Young, Teresa Szal, N. Vázquez-Laslop, A. Mankin, James S. Fraser, D. Fujimori","doi":"10.1101/2021.08.10.455846","DOIUrl":"https://doi.org/10.1101/2021.08.10.455846","url":null,"abstract":"The antibiotic linezolid, the first clinically approved member of the oxazolidinone class, inhibits translation of bacterial ribosomes by binding to the peptidyl transferase center. Recent work has demonstrated that linezolid does not inhibit peptide bond formation at all sequences but rather acts in a context-specific manner, namely when alanine occupies the penultimate position of the nascent chain. In this study, we determined that the second-generation oxazolidinone radezolid also induces stalling with alanine at the penultimate position. However, the molecular basis for context-specificity of these inhibitors has not been elucidated. In this study, we determined high-resolution cryo-EM structures of both linezolid and radezolid-stalled ribosome complexes. These structures reveal that the alanine side chain fits within a small hydrophobic crevice created by oxazolidinone, resulting in improved ribosome binding. Modification of the ribosome by the antibiotic resistance enzyme Cfr disrupts stalling by forcing the antibiotic to adopt a conformation that narrows the hydrophobic alanine pocket. Together, the structural and biochemical findings presented in this work provide molecular understanding of context-specific inhibition of translation by clinically important oxazolidinone antibiotics.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"1 1","pages":""},"PeriodicalIF":16.8,"publicationDate":"2021-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"62332424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Higher-order phosphatase–substrate contacts terminate the integrated stress response 高阶磷酸酶-底物接触终止了综合应力响应
IF 16.8 1区 生物学
Nature Structural &Molecular Biology Pub Date : 2021-06-18 DOI: 10.1101/2021.06.18.449003
Yahui Yan, H. Harding, D. Ron
{"title":"Higher-order phosphatase–substrate contacts terminate the integrated stress response","authors":"Yahui Yan, H. Harding, D. Ron","doi":"10.1101/2021.06.18.449003","DOIUrl":"https://doi.org/10.1101/2021.06.18.449003","url":null,"abstract":"Many regulatory PPP1R subunits join few catalytic PP1c subunits to mediate phosphoserine and phosphothreonine dephosphorylation in metazoans. Regulatory subunits engage the surface of PP1c, locally affecting flexible access of the phosphopeptide to the active site. However, catalytic efficiency of holophosphatases towards their phosphoprotein substrates remains unexplained. Here we present a cryo-EM structure of the tripartite PP1c–PPP1R15A–G-actin holophosphatase that terminates signaling in the mammalian integrated stress response (ISR) in the pre-dephosphorylation complex with its substrate, translation initiation factor 2α (eIF2α). G-actin, whose essential role in eIF2α dephosphorylation is supported crystallographically, biochemically and genetically, aligns the catalytic and regulatory subunits, creating a composite surface that engages the N-terminal domain of eIF2α to position the distant phosphoserine-51 at the active site. Substrate residues that mediate affinity for the holophosphatase also make critical contacts with eIF2α kinases. Thus, a convergent process of higher-order substrate recognition specifies functionally antagonistic phosphorylation and dephosphorylation in the ISR. Structures of the dephosphorylation complex for phosphorylated eIF2α reveal how contacts with the regulatory PPP1R15A subunit mediate substrate selectivity, providing a paradigm for dephosphorylation reactions by diverse combinatorially assembled holophosphatases.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"28 1","pages":"835 - 846"},"PeriodicalIF":16.8,"publicationDate":"2021-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49110087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 6
Structural basis of nucleosome transcription mediated by Chd1 and FACT Chd1和FACT介导核小体转录的结构基础
IF 16.8 1区 生物学
Nature Structural &Molecular Biology Pub Date : 2020-11-30 DOI: 10.1101/2020.11.30.403857
L. Farnung, M. Ochmann, M. Engeholm, P. Cramer
{"title":"Structural basis of nucleosome transcription mediated by Chd1 and FACT","authors":"L. Farnung, M. Ochmann, M. Engeholm, P. Cramer","doi":"10.1101/2020.11.30.403857","DOIUrl":"https://doi.org/10.1101/2020.11.30.403857","url":null,"abstract":"Efficient transcription of RNA polymerase II (Pol II) through nucleosomes requires the help of various factors. Here we show biochemically that Pol II transcription through a nucleosome is facilitated by the chromatin remodeler Chd1 and the histone chaperone FACT when the elongation factors Spt4/5 and TFIIS are present. We report cryo-EM structures of transcribing Saccharomyces cerevisiae Pol II−Spt4/5−nucleosome complexes with bound Chd1 or FACT. In the first structure, Pol II transcription exposes the proximal histone H2A−H2B dimer that is bound by Spt5. Pol II has also released the inhibitory DNA-binding region of Chd1 that is poised to pump DNA toward Pol II. In the second structure, Pol II has generated a partially unraveled nucleosome that binds FACT, which excludes Chd1 and Spt5. These results suggest that Pol II progression through a nucleosome activates Chd1, enables FACT binding and eventually triggers transfer of FACT together with histones to upstream DNA. Structural and functional analyses of RNA polymerase II−nucleosome complexes reveal how the chromatin remodeler Chd1 and the histone chaperone FACT mediate Pol II transcription through a nucleosome.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"28 1","pages":"382 - 387"},"PeriodicalIF":16.8,"publicationDate":"2020-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42190486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 55
Cryo-EM structures of human RNA polymerase III in its unbound and transcribing states 人RNA聚合酶III非结合状态和转录状态的低温电镜结构
IF 16.8 1区 生物学
Nature Structural &Molecular Biology Pub Date : 2020-06-29 DOI: 10.1101/2020.06.29.177642
M. Girbig, A. Misiaszek, Matthias K. Vorländer, Aleix Lafita, H. Grötsch, F. Baudin, A. Bateman, C. Müller
{"title":"Cryo-EM structures of human RNA polymerase III in its unbound and transcribing states","authors":"M. Girbig, A. Misiaszek, Matthias K. Vorländer, Aleix Lafita, H. Grötsch, F. Baudin, A. Bateman, C. Müller","doi":"10.1101/2020.06.29.177642","DOIUrl":"https://doi.org/10.1101/2020.06.29.177642","url":null,"abstract":"RNA polymerase III (Pol III) synthesizes transfer RNAs and other short, essential RNAs. Human Pol III misregulation is linked to tumor transformation, neurodegenerative and developmental disorders, and increased sensitivity to viral infections. Here, we present cryo-electron microscopy structures at 2.8 to 3.3 Å resolution of transcribing and unbound human Pol III. We observe insertion of the TFIIS-like subunit RPC10 into the polymerase funnel, providing insights into how RPC10 triggers transcription termination. Our structures resolve elements absent from Saccharomyces cerevisiae Pol III such as the winged-helix domains of RPC5 and an iron–sulfur cluster, which tethers the heterotrimer subcomplex to the core. The cancer-associated RPC7α isoform binds the polymerase clamp, potentially interfering with Pol III inhibition by tumor suppressor MAF1, which may explain why overexpressed RPC7α enhances tumor transformation. Finally, the human Pol III structure allows mapping of disease-related mutations and may contribute to the development of inhibitors that selectively target Pol III for therapeutic interventions. Cryo-EM structures of human Pol III in both apo- and elongating states reveal metazoan-specific differences in the regulation of transcription termination and identify mutations relevant to human disease.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"28 1","pages":"210 - 219"},"PeriodicalIF":16.8,"publicationDate":"2020-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42310095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 40
Structural and functional characterization of the Spo11 core complex Spo11核配合物的结构与功能表征
IF 16.8 1区 生物学
Nature Structural &Molecular Biology Pub Date : 2020-02-24 DOI: 10.1101/2020.02.21.960211
Corentin Claeys Bouuaert, Sam E. Tischfield, Stephen Pu, Eleni P. Mimitou, E. Arias-Palomo, J. Berger, S. Keeney
{"title":"Structural and functional characterization of the Spo11 core complex","authors":"Corentin Claeys Bouuaert, Sam E. Tischfield, Stephen Pu, Eleni P. Mimitou, E. Arias-Palomo, J. Berger, S. Keeney","doi":"10.1101/2020.02.21.960211","DOIUrl":"https://doi.org/10.1101/2020.02.21.960211","url":null,"abstract":"Spo11, which makes DNA double-strand breaks (DSBs) that are essential for meiotic recombination, has long been recalcitrant to biochemical study. We provide molecular analysis of Saccharomyces cerevisiae Spo11 purified with partners Rec102, Rec104 and Ski8. Rec102 and Rec104 jointly resemble the B subunit of archaeal topoisomerase VI, with Rec104 occupying a position similar to the Top6B GHKL-type ATPase domain. Unexpectedly, the Spo11 complex is monomeric (1:1:1:1 stoichiometry), consistent with dimerization controlling DSB formation. Reconstitution of DNA binding reveals topoisomerase-like preferences for duplex–duplex junctions and bent DNA. Spo11 also binds noncovalently but with high affinity to DNA ends mimicking cleavage products, suggesting a mechanism to cap DSB ends. Mutations that reduce DNA binding in vitro attenuate DSB formation, alter DSB processing and reshape the DSB landscape in vivo. Our data reveal structural and functional similarities between the Spo11 core complex and Topo VI, but also highlight differences reflecting their distinct biological roles. Biochemical and structural characterization of the meiotic DSB core complex of budding yeast reveals molecular architecture and DNA-binding properties similar to those of ancestral Topo VI.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"28 1","pages":"92 - 102"},"PeriodicalIF":16.8,"publicationDate":"2020-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49195616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 27
Engaging the public 让公众参与
IF 16.8 1区 生物学
Nature Structural &Molecular Biology Pub Date : 2020-01-16 DOI: 10.1201/9781315384467-5
Emily Troshynski
{"title":"Engaging the public","authors":"Emily Troshynski","doi":"10.1201/9781315384467-5","DOIUrl":"https://doi.org/10.1201/9781315384467-5","url":null,"abstract":"Introduction In Chapter 2 we discussed the fundamentals of visioning and building a strong collaborative partnership—especially among key local agencies and organizations. But members of the public at large also need and increasingly want to reconnect with their community through food and agriculture—whether as voters, tourists or farm neighbors. In this section we describe some strategies for engaing the public in local food and agriculture system development.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"39 1","pages":"1287-1287"},"PeriodicalIF":16.8,"publicationDate":"2020-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74000721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 27
Structure of ACLY in complex with CoA ACLY与辅酶A复合物的结构
IF 16.8 1区 生物学
Nature Structural &Molecular Biology Pub Date : 2019-12-25 DOI: 10.2210/pdb6poe/pdb
Xuepeng Wei, Kollin Schultz, Gleb A. Bazilevsky, Austin D. Vogt, R. Marmorstein
{"title":"Structure of ACLY in complex with CoA","authors":"Xuepeng Wei, Kollin Schultz, Gleb A. Bazilevsky, Austin D. Vogt, R. Marmorstein","doi":"10.2210/pdb6poe/pdb","DOIUrl":"https://doi.org/10.2210/pdb6poe/pdb","url":null,"abstract":"ATP-citrate lyase (ACLY) synthesizes cytosolic acetyl coenzyme A (acetyl-CoA), a fundamental cellular building block. Accordingly, aberrant ACLY activity is observed in many diseases. Here we report cryo-EM structures of human ACLY, alone or bound to substrates or products. ACLY forms a homotetramer with a rigid citrate synthase homology (CSH) module, flanked by four flexible acetyl-CoA synthetase homology (ASH) domains; CoA is bound at the CSH-ASH interface in mutually exclusive productive or unproductive conformations. The structure of a catalytic mutant of ACLY in the presence of ATP, citrate and CoA substrates reveals a phospho-citryl-CoA intermediate in the ASH domain. ACLY with acetyl-CoA and oxaloacetate products shows the products bound in the ASH domain, with an additional oxaloacetate in the CSH domain, which could function in ACLY autoinhibition. These structures, which are supported by biochemical and biophysical data, challenge previous proposals of the ACLY catalytic mechanism and suggest additional therapeutic possibilities for ACLY-associated metabolic disorders.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"27 1","pages":"33-41"},"PeriodicalIF":16.8,"publicationDate":"2019-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44608200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
MERS-CoV S structure in complex with 2,3-sialyl-N-acetyl-lactosamine MERS-CoV与2,3-唾液酰- n -乙酰-乳胺配合物的结构
IF 16.8 1区 生物学
Nature Structural &Molecular Biology Pub Date : 2019-12-11 DOI: 10.2210/pdb6q06/pdb
Y. Park, A. Walls, Z. Wang, M. Sauer, W. Li, M. Tortorici, B. Bosch, F. DiMaio, D. Veesler
{"title":"MERS-CoV S structure in complex with 2,3-sialyl-N-acetyl-lactosamine","authors":"Y. Park, A. Walls, Z. Wang, M. Sauer, W. Li, M. Tortorici, B. Bosch, F. DiMaio, D. Veesler","doi":"10.2210/pdb6q06/pdb","DOIUrl":"https://doi.org/10.2210/pdb6q06/pdb","url":null,"abstract":"","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":"1 1","pages":""},"PeriodicalIF":16.8,"publicationDate":"2019-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68201933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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