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

Multiple steps of dynein activation by Lis1 visualized by cryo-EM 低温电镜观察Lis1激活动力蛋白的多个步骤

Nature structural & molecular biology Pub Date : 2025-05-23 DOI: 10.1038/s41594-025-01558-w

Agnieszka A. Kendrick, Kendrick H. V. Nguyen, Wen Ma, Eva P. Karasmanis, Rommie E. Amaro, Samara L. Reck-Peterson, Andres E. Leschziner

{"title":"Multiple steps of dynein activation by Lis1 visualized by cryo-EM","authors":"Agnieszka A. Kendrick, Kendrick H. V. Nguyen, Wen Ma, Eva P. Karasmanis, Rommie E. Amaro, Samara L. Reck-Peterson, Andres E. Leschziner","doi":"10.1038/s41594-025-01558-w","DOIUrl":"https://doi.org/10.1038/s41594-025-01558-w","url":null,"abstract":"Cytoplasmic dynein-1 (dynein) is an essential molecular motor controlled in part by autoinhibition. Lis1, a key dynein regulator mutated in the neurodevelopmental disease lissencephaly, plays a role in dynein activation. We recently identified a structure of partially autoinhibited dynein bound to Lis1, which suggests an intermediate state in dynein’s activation pathway. However, other structural information is needed to fully understand how Lis1 activates dynein. Here, we used cryo-EM and yeast dynein and Lis1 incubated with ATP at different time points to reveal conformations that we propose represent additional intermediate states in dynein’s activation pathway. We solved 16 high-resolution structures, including 7 distinct dynein and dynein–Lis1 structures from the same sample. Our data support a model in which Lis1 relieves dynein autoinhibition by increasing its basal ATP hydrolysis rate and promoting conformations compatible with complex assembly and motility. Together, this analysis advances our understanding of dynein activation and the contribution of Lis1 to this process.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"238 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123075","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

Structural elucidation of full-length Pfs48/45 in complex with potent monoclonal antibodies isolated from a naturally exposed individual 从自然暴露个体中分离的强效单克隆抗体复合物全长Pfs48/45的结构解析

Nature structural & molecular biology Pub Date : 2025-05-22 DOI: 10.1038/s41594-025-01532-6

Iga Kucharska, Danton Ivanochko, Sophia Hailemariam, Maartje R. Inklaar, Hee Ryung Kim, Karina Teelen, Rianne Stoter, Marga van de Vegte-Bolmer, Geert-Jan van Gemert, Anthony Semesi, Brandon McLeod, Ahyoung Ki, Won-Kyu Lee, John L. Rubinstein, Matthijs M. Jore, Jean-Philippe Julien

{"title":"Structural elucidation of full-length Pfs48/45 in complex with potent monoclonal antibodies isolated from a naturally exposed individual","authors":"Iga Kucharska, Danton Ivanochko, Sophia Hailemariam, Maartje R. Inklaar, Hee Ryung Kim, Karina Teelen, Rianne Stoter, Marga van de Vegte-Bolmer, Geert-Jan van Gemert, Anthony Semesi, Brandon McLeod, Ahyoung Ki, Won-Kyu Lee, John L. Rubinstein, Matthijs M. Jore, Jean-Philippe Julien","doi":"10.1038/s41594-025-01532-6","DOIUrl":"https://doi.org/10.1038/s41594-025-01532-6","url":null,"abstract":"Biomedical interventions that block the transmission of Plasmodium falciparum (Pf) from humans to mosquitoes may be critical for malaria elimination. Pfs48/45, a gamete-surface protein essential for Pf development in the mosquito midgut, is a target of clinical-stage transmission-blocking vaccines and monoclonal antibodies (mAbs) that disrupt Pf transmission to mosquitoes. Antibodies directed to domain 3 of Pfs48/45 have been structurally and functionally described; however, in-depth information about other inhibitory epitopes on Pfs48/45 is currently limited. Here, we present a cryo-electron microscopy structure of full-length Pfs48/45 in complex with potent human mAbs targeting all three domains. Our data indicate that although Pfs48/45 domains 1 and 2 are rigidly coupled, there is substantial conformational flexibility between domains 2 and 3. Characterization of mAbs against domain 1 revealed the presence of a conformational epitope class that is largely conserved across Pf field isolates and is associated with recognition by potent antibodies. Our study provides insights into epitopes across full-length Pfs48/45 and has implications for the design of next-generation malaria interventions.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113819","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

Making 3′ ends meet 收支相抵

Nature structural & molecular biology Pub Date : 2025-05-22 DOI: 10.1038/s41594-025-01578-6

Sylvie Doublié

引用次数: 0

The yin yang of transcriptional memory 转录记忆的阴阳

Nature structural & molecular biology Pub Date : 2025-05-21 DOI: 10.1038/s41594-025-01574-w

Alejandra Laguillo-Diego, Effie Apostolou

引用次数: 0

Structure, assembly and inhibition of the Toxoplasma gondii respiratory chain supercomplex 刚地弓形虫呼吸链超复合体的结构、组装及抑制作用

Nature structural & molecular biology Pub Date : 2025-05-19 DOI: 10.1038/s41594-025-01531-7

Andrew E. MacLean, Shikha Shikha, Mariana Ferreira Silva, Max J. Gramelspacher, Aaron Nilsen, Katherine M. Liebman, Sovitj Pou, Rolf W. Winter, Amit Meir, Michael K. Riscoe, J. Stone Doggett, Lilach Sheiner, Alexander Mühleip

{"title":"Structure, assembly and inhibition of the Toxoplasma gondii respiratory chain supercomplex","authors":"Andrew E. MacLean, Shikha Shikha, Mariana Ferreira Silva, Max J. Gramelspacher, Aaron Nilsen, Katherine M. Liebman, Sovitj Pou, Rolf W. Winter, Amit Meir, Michael K. Riscoe, J. Stone Doggett, Lilach Sheiner, Alexander Mühleip","doi":"10.1038/s41594-025-01531-7","DOIUrl":"https://doi.org/10.1038/s41594-025-01531-7","url":null,"abstract":"The apicomplexan mitochondrial electron transport chain is essential for parasite survival and displays a divergent subunit composition. Here we report cryo-electron microscopy structures of an apicomplexan III2–IV supercomplex and of the drug target complex III2. The supercomplex structure reveals how clade-specific subunits form an apicomplexan-conserved III2–IV interface with a unique, kinked architecture, suggesting that supercomplexes evolved independently in different eukaryotic lineages. A knockout resulting in supercomplex disassembly challenges the proposed role of III2–IV in electron transfer efficiency as suggested for mammals. Nevertheless, knockout analysis indicates that III2–IV is critical for parasite fitness. The complexes from the model parasite Toxoplasma gondii were inhibited with the antimalarial atovaquone, revealing interactions underpinning species specificity. They were also inhibited with endochin-like quinolone (ELQ)-300, an inhibitor in late-stage preclinical development. Notably, in the apicomplexan binding site, ELQ-300 is flipped compared with related compounds in the mammalian enzyme. On the basis of the binding modes and parasite-specific interactions discovered, we designed more potent ELQs with subnanomolar activity against T. gondii. Our findings reveal critical evolutionary differences in the role of supercomplexes in mitochondrial biology and provide insight into cytochrome b inhibition, informing future drug discovery.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144087882","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

How we peer review structural data 我们如何对结构数据进行同行评审

Nature structural & molecular biology Pub Date : 2025-05-19 DOI: 10.1038/s41594-025-01567-9

引用次数: 0

DEK–nucleosome structure shows DEK modulates H3K27me3 and stem cell fate DEK -核小体结构显示DEK调节H3K27me3和干细胞命运

Nature structural & molecular biology Pub Date : 2025-05-16 DOI: 10.1038/s41594-025-01559-9

Yunfan Shen, Yanhong Liu, Maochao Guo, Song Mao, Rui Chen, Mengran Wang, Zhengbo Li, Yue Li, Wan Chen, Fang Chen, Baixing Wu, Chongyuan Wang, Wei Chen, Huanhuan Cui, Kai Yuan, Hongda Huang

{"title":"DEK–nucleosome structure shows DEK modulates H3K27me3 and stem cell fate","authors":"Yunfan Shen, Yanhong Liu, Maochao Guo, Song Mao, Rui Chen, Mengran Wang, Zhengbo Li, Yue Li, Wan Chen, Fang Chen, Baixing Wu, Chongyuan Wang, Wei Chen, Huanhuan Cui, Kai Yuan, Hongda Huang","doi":"10.1038/s41594-025-01559-9","DOIUrl":"https://doi.org/10.1038/s41594-025-01559-9","url":null,"abstract":"DEK is a highly conserved chromatin-associated oncoprotein that has important roles in regulating chromatin dynamics and stem cell fate. Dysregulation of DEK is associated with stem cell dysfunction and cancers, including acute myeloid leukemia. Despite its importance in chromatin regulation, the structural mechanisms underlying DEK’s interaction with chromatin and its influence on gene regulation remain poorly understood. Here we combined cryogenic electron microscopy (cryo-EM), biochemical and cellular approaches to investigate the molecular mechanisms and functional importance of DEK’s interaction with chromatin. Our cryo-EM structures reveal the structural basis of the DEK–nucleosome interaction. Biochemical and cellular results demonstrate that this interaction is crucial for DEK deposition onto chromatin. Furthermore, our results reveal that DEK safeguards mouse embryonic stem cells from acquiring primitive endoderm fates by modulating the repressive histone mark H3K27me3. Together, our study provides crucial molecular insights into the structure and function of DEK, establishing a framework for understanding its roles in chromatin biology and cell fate determination.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144066267","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

The importance of physiological and disease contexts in capturing mRNA modifications 生理和疾病背景在捕获mRNA修饰中的重要性

Nature structural & molecular biology Pub Date : 2025-05-16 DOI: 10.1038/s41594-025-01548-y

Audrey Penning, François Fuks

引用次数: 0

Jerelle Joseph: seeing biomolecular condensates with computation Jerelle Joseph：用计算来观察生物分子凝聚

Nature structural & molecular biology Pub Date : 2025-05-16 DOI: 10.1038/s41594-025-01564-y

Melina Casadio

引用次数: 0

Structural clues about bridge-mediated lipid transfer 桥介导的脂质转移的结构线索

Nature structural & molecular biology Pub Date : 2025-05-15 DOI: 10.1038/s41594-025-01552-2

Pietro De Camilli, Karin M. Reinisch

引用次数: 0