Nature structural & molecular biology最新文献_第2页

Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control 比较CRISPRi筛选揭示了人类干细胞对mRNA翻译耦合质量控制的依赖

Nature structural & molecular biology Pub Date : 2025-07-11 DOI: 10.1038/s41594-025-01616-3

Geraldine Rodschinka, Sergio Forcelloni, Felix M. Kühner, Sascha Wani, Henrick Riemenschneider, Dieter Edbauer, Andrew Behrens, Danny D. Nedialkova

{"title":"Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control","authors":"Geraldine Rodschinka, Sergio Forcelloni, Felix M. Kühner, Sascha Wani, Henrick Riemenschneider, Dieter Edbauer, Andrew Behrens, Danny D. Nedialkova","doi":"10.1038/s41594-025-01616-3","DOIUrl":"https://doi.org/10.1038/s41594-025-01616-3","url":null,"abstract":"The translation of mRNA into proteins in multicellular organisms needs to be carefully tuned to changing proteome demands in development and differentiation, while defects in translation often have a disproportionate impact in distinct cell types. Here we used inducible CRISPR interference screens to compare the essentiality of genes with functions in mRNA translation in human induced pluripotent stem cells (hiPS cells) and hiPS cell-derived neural and cardiac cells. We find that core components of the mRNA translation machinery are broadly essential but the consequences of perturbing translation-coupled quality control factors are cell type dependent. Human stem cells critically depend on pathways that detect and rescue slow or stalled ribosomes and on the E3 ligase ZNF598 to resolve a distinct type of ribosome collision at translation start sites on endogenous mRNAs with highly efficient initiation. Our findings underscore the importance of cell identity for deciphering the molecular mechanisms of translational control in metazoans.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144603347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

V-ATPase assembly at leaky lysosomes 漏溶酶体上的v - atp酶组装

Nature structural & molecular biology Pub Date : 2025-07-11 DOI: 10.1038/s41594-025-01612-7

Alf Håkon Lystad

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Neuronal VPS13D loss drives microglial activation 神经元VPS13D缺失驱动小胶质细胞激活

Nature structural & molecular biology Pub Date : 2025-07-11 DOI: 10.1038/s41594-025-01623-4

Himanish Basu, Coco Holliday, Isaac M. Chiu

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A marker for sterol-dependent metastatic tropism 胆固醇依赖性转移性的标志物

Nature structural & molecular biology Pub Date : 2025-07-11 DOI: 10.1038/s41594-025-01626-1

Yuqi Wang, Xi Wang, Charles J. David, Yilong Zou

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Author Correction: The importance of physiological and disease contexts in capturing mRNA modifications. 作者更正：生理和疾病背景在捕获mRNA修饰中的重要性。

Nature structural & molecular biology Pub Date : 2025-07-11 DOI: 10.1038/s41594-025-01637-y

Audrey Penning,Jana Jeschke,François Fuks

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Ferlin structures Ferlin结构。

Nature structural & molecular biology Pub Date : 2025-07-09 DOI: 10.1038/s41594-025-01624-3

Suhaila Rahman

引用次数: 0

Structure-guided molecular glues 结构导向分子胶

Nature structural & molecular biology Pub Date : 2025-07-09 DOI: 10.1038/s41594-025-01627-0

Antonio R. Cerullo

{"title":"Structure-guided molecular glues","authors":"Antonio R. Cerullo","doi":"10.1038/s41594-025-01627-0","DOIUrl":"https://doi.org/10.1038/s41594-025-01627-0","url":null,"abstract":"Targeted protein degradation is a proven paradigm for advancing the fields of drug discovery, biochemical regulatory networks, and proteostasis. Although several targeting strategies exist, molecular glues — small molecules that stabilize endogenous or non-native protein–protein interactions — are enticing because of their versatility, high cellular uptake and desirable pharmacological properties. Inducing protein degradation is a promising translational approach, particularly for targeting the classically ‘undruggable’ proteome. In RSC Chemical Biology, Ghosh et al. use X-ray crystal structures to inspire the de novo design of molecular glues with potential as future cancer therapies.The authors determined the mechanism of action for the CDK12 inhibitor, SR-4835. The compound acts as a molecular glue that stabilizes interactions between CDK12 and its adaptor protein, DDB1, facilitating proteasomal degradation. By solving the DDB1–SR-4835–CDK12–cyclin K ternary complex structure, the authors leveraged knowledge of the protein–protein interaction interfaces to design molecular glues by converting established CDK12 inhibitors into potent cyclin K degraders. SR-4835 was found to occupy the binding pocket in CDK12 and bridged the protein complex through its benzimidazole ring; this benzimidazole moiety was appended onto the CDK12 inhibitor dinaciclib, which, in turn, induced degradation of cyclin K. The authors applied this approach to other purine scaffolds, finding that they degraded their target with varying potency. Interestingly, functional analysis revealed that while these glues induced degradation through complex formation, they did not considerably affect enzymatic activity. In vivo proteome-wide degradation analysis confirmed that the compounds selectively degraded cyclin K, validating that their chemical design approach yields successful drug candidates in a biological context.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"109 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A nanobody-based therapeutic targeting Nipah virus limits viral escape 一种基于纳米体的治疗尼帕病毒的方法限制了病毒的逃逸

Nature structural & molecular biology Pub Date : 2025-07-08 DOI: 10.1038/s41594-025-01598-2

Ariel Isaacs, Guillermo Valenzuela Nieto, Xinghai Zhang, Naphak Modhiran, Jennifer Barr, Nazia Thakur, Yu Shang Low, Rhys H. Parry, James B. Barnes, Ronald Jara, Johanna Himelreichs, Yanfeng Yao, Camila Deride, Barbara Barthou-Gatica, Constanza Salinas-Rebolledo, Pamela Ehrenfeld, Jun Jet Hen, Noah Hayes, Devina Paramitha, Mahali S. Morgan, Christopher L. D. McMillan, Martina L. Jones, Trent P. Munro, Alexander A. Khromykh, Patrick C. Reading, Paul R. Young, Keith J. Chappell, Yi Shi, Dalan Bailey, Glenn A. Marsh, Sandra Chiu, Alejandro Rojas-Fernandez, Daniel Watterson

{"title":"A nanobody-based therapeutic targeting Nipah virus limits viral escape","authors":"Ariel Isaacs, Guillermo Valenzuela Nieto, Xinghai Zhang, Naphak Modhiran, Jennifer Barr, Nazia Thakur, Yu Shang Low, Rhys H. Parry, James B. Barnes, Ronald Jara, Johanna Himelreichs, Yanfeng Yao, Camila Deride, Barbara Barthou-Gatica, Constanza Salinas-Rebolledo, Pamela Ehrenfeld, Jun Jet Hen, Noah Hayes, Devina Paramitha, Mahali S. Morgan, Christopher L. D. McMillan, Martina L. Jones, Trent P. Munro, Alexander A. Khromykh, Patrick C. Reading, Paul R. Young, Keith J. Chappell, Yi Shi, Dalan Bailey, Glenn A. Marsh, Sandra Chiu, Alejandro Rojas-Fernandez, Daniel Watterson","doi":"10.1038/s41594-025-01598-2","DOIUrl":"https://doi.org/10.1038/s41594-025-01598-2","url":null,"abstract":"Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic henipaviruses without approved human vaccines or therapies. Here, we report on a highly potent bispecific therapeutic that combines an anti-fusion glycoprotein nanobody with an anti-receptor-binding glycoprotein (RBP) antibody to deliver a dual-targeting biologic that is resistant to viral escape. We show that the nanobody, DS90, engages a unique, conserved site within the fusion glycoprotein of NiV and HeV and provides neutralization and complete protection from NiV disease. Bispecific engineering of DS90 with the anti-RBP monoclonal antibody m102.4 results in neutralization, elimination of viral escape and superior protection from NiV disease compared to leading monovalent approaches. These findings carry implications for the development of cross-neutralizing immunotherapies that limit the emergence of henipaviral escape mutants.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"90 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144578076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glycerol mediates crosstalk between metabolism and trafficking through the golgin Imh1 甘油通过golgin Imh1介导代谢和运输之间的串扰

Nature structural & molecular biology Pub Date : 2025-07-08 DOI: 10.1038/s41594-025-01600-x

Wan-Yun Chiu, Yi-Hsun Wang, Ming-Chieh Lin, Chun-Chi Lai, Chia-Jung Yu, Fang-Jen S. Lee

引用次数: 0

Structural basis of RECQL5-induced RNA polymerase II transcription braking and subsequent reactivation recql5诱导RNA聚合酶II转录抑制及随后再激活的结构基础

Nature structural & molecular biology Pub Date : 2025-07-07 DOI: 10.1038/s41594-025-01586-6

Luojia Zhang, Yuliya Gordiyenko, Tomos Morgan, Catarina Franco, Ana Tufegdžić Vidaković, Suyang Zhang

{"title":"Structural basis of RECQL5-induced RNA polymerase II transcription braking and subsequent reactivation","authors":"Luojia Zhang, Yuliya Gordiyenko, Tomos Morgan, Catarina Franco, Ana Tufegdžić Vidaković, Suyang Zhang","doi":"10.1038/s41594-025-01586-6","DOIUrl":"https://doi.org/10.1038/s41594-025-01586-6","url":null,"abstract":"Abnormally fast transcription elongation can lead to detrimental consequences such as transcription–replication collisions, altered alternative splicing patterns and genome instability. Therefore, elongating RNA polymerase II (Pol II) requires mechanisms to slow its progression, yet the molecular basis of transcription braking remains unclear. RECQL5 is a DNA helicase that functions as a general elongation factor by slowing down Pol II. Here we report cryo-electron microscopy structures of human RECQL5 bound to multiple transcription elongation complexes. Combined with biochemical analysis, we identify an α-helix of RECQL5 responsible for binding Pol II and slowdown of transcription elongation. We further reveal that the transcription-coupled DNA repair (TCR) complex allows Pol II to overcome RECQL5-induced transcription braking through concerted actions of its translocase activity and competition with RECQL5 for engaging Pol II. Additionally, RECQL5 inhibits TCR-mediated Pol II ubiquitination to prevent activation of the DNA repair pathway. Our results suggest a model in which RECQL5 and the TCR complex coordinately regulate transcription elongation rates to ensure transcription efficiency while maintaining genome stability.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"108 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0