Nature structural & molecular biology最新文献

Slow awakening of the silent X chromosome in female primordial germ cells 雌性原始生殖细胞中沉默的X染色体的缓慢觉醒

Nature structural & molecular biology Pub Date : 2025-05-05 DOI: 10.1038/s41594-025-01550-4

Christine M. Disteche, Xinxian Deng

引用次数: 0

Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30 嵌合去泛素酶工程揭示了特异性抑制线粒体自噬调节因子USP30的结构基础

Nature structural & molecular biology Pub Date : 2025-05-05 DOI: 10.1038/s41594-025-01534-4

Nafizul Haque Kazi, Nikolas Klink, Kai Gallant, Gian-Marvin Kipka, Malte Gersch

{"title":"Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30","authors":"Nafizul Haque Kazi, Nikolas Klink, Kai Gallant, Gian-Marvin Kipka, Malte Gersch","doi":"10.1038/s41594-025-01534-4","DOIUrl":"https://doi.org/10.1038/s41594-025-01534-4","url":null,"abstract":"The mitochondrial deubiquitinase ubiquitin-specific protease (USP) 30 negatively regulates PINK1–parkin-driven mitophagy. Whether enhanced mitochondrial quality control through inhibition of USP30 can protect dopaminergic neurons is currently being explored in a clinical trial for Parkinson’s disease. However, the molecular basis for specific inhibition of USP30 by small molecules has remained elusive. Here we report the crystal structure of human USP30 in complex with a specific inhibitor, enabled by chimeric protein engineering. Our study uncovers how the inhibitor extends into a cryptic pocket facilitated by a compound-induced conformation of the USP30 switching loop. Our work underscores the potential of exploring induced pockets and conformational dynamics to obtain deubiquitinase inhibitors and identifies residues facilitating specific inhibition of USP30. More broadly, we delineate a conceptual framework for specific USP deubiquitinase inhibition based on a common ligandability hotspot in the Leu73 ubiquitin binding site and on diverse compound extensions. Collectively, our work establishes a generalizable chimeric protein-engineering strategy to aid deubiquitinase crystallization and enables structure-based drug design with relevance to neurodegeneration.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910288","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

piRNA gene density and SUMOylation organize piRNA transcriptional condensate formation piRNA基因密度和sumo化作用组织piRNA转录凝聚物的形成

Nature structural & molecular biology Pub Date : 2025-05-02 DOI: 10.1038/s41594-025-01533-5

Chengming Zhu, Xiaoyue Si, Xinhao Hou, Panpan Xu, Jianing Gao, Yao Tang, Chenchun Weng, Mingjing Xu, Qi Yan, Qile Jin, Jiewei Cheng, Ke Ruan, Ying Zhou, Ge Shan, Demin Xu, Xiangyang Chen, Shengqi Xiang, Xinya Huang, Xuezhu Feng, Shouhong Guang

{"title":"piRNA gene density and SUMOylation organize piRNA transcriptional condensate formation","authors":"Chengming Zhu, Xiaoyue Si, Xinhao Hou, Panpan Xu, Jianing Gao, Yao Tang, Chenchun Weng, Mingjing Xu, Qi Yan, Qile Jin, Jiewei Cheng, Ke Ruan, Ying Zhou, Ge Shan, Demin Xu, Xiangyang Chen, Shengqi Xiang, Xinya Huang, Xuezhu Feng, Shouhong Guang","doi":"10.1038/s41594-025-01533-5","DOIUrl":"https://doi.org/10.1038/s41594-025-01533-5","url":null,"abstract":"Piwi-interacting RNAs (piRNAs) are essential for maintaining genome integrity and fertility in various organisms. In flies and nematodes, piRNA genes are encoded in heterochromatinized genomic clusters. The molecular mechanisms of piRNA transcription remain intriguing. Through small RNA sequencing and chromatin editing, we discovered that spatial aggregation of piRNA genes enhances their transcription in nematodes. The facultative heterochromatinized piRNA genome recruits the piRNA upstream sequence transcription complex (USTC; including PRDE-1, SNPC4, TOFU-4 and TOFU-5) and the H3K27me3 reader UAD-2, which phase-separate into droplets to initiate piRNA transcription. We searched for factors that regulate piRNA transcription and isolated the SUMO E3 ligase GEI-17 as inhibiting and the SUMO protease TOFU-3 as promoting piRNA transcription foci formation, thereby regulating piRNA production. Our study revealed that spatial aggregation of piRNA genes, phase separation and deSUMOylation may benefit the organization of functional biomolecular condensates to direct piRNA transcription in the facultative heterochromatinized genome.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143898139","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

Gating mechanism of the two-pore-domain potassium channel THIK1 双孔域钾通道THIK1的门控机制

Nature structural & molecular biology Pub Date : 2025-04-30 DOI: 10.1038/s41594-025-01542-4

Xiangyun Fang, Haichao Jin, Jin Wang, Ran Zhang, Baobin Li

引用次数: 0

Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation 利用E3连接酶GID4进行靶向蛋白降解的PROTACs设计

Nature structural & molecular biology Pub Date : 2025-04-28 DOI: 10.1038/s41594-025-01537-1

Yanran Li, Kaiwen Bao, Jiyue Sun, Ruixin Ge, Qiqing Zhang, Bing Zhang, Xiaojie Yan, Junlin Li, Fengying Shi, Meiling Zhang, Jinzhi Zang, Min Liu, Jun Zhou, Wenyi Mi, Songbo Xie, Dongxing Chen, Lei Shi, Cheng Dong

{"title":"Design of PROTACs utilizing the E3 ligase GID4 for targeted protein degradation","authors":"Yanran Li, Kaiwen Bao, Jiyue Sun, Ruixin Ge, Qiqing Zhang, Bing Zhang, Xiaojie Yan, Junlin Li, Fengying Shi, Meiling Zhang, Jinzhi Zang, Min Liu, Jun Zhou, Wenyi Mi, Songbo Xie, Dongxing Chen, Lei Shi, Cheng Dong","doi":"10.1038/s41594-025-01537-1","DOIUrl":"https://doi.org/10.1038/s41594-025-01537-1","url":null,"abstract":"Proteolysis targeting chimeras (PROTACs) hijack E3 ligases and the ubiquitin–proteasome system to achieve selective degradation of neo-substrates. Their ability to target otherwise intractable substrates has rendered them a valuable modality in drug discovery. However, only a handful of over 600 human E3 ligases have been functionalized for PROTAC applications. Here we show that the E3 ligase GID4 (glucose-induced degradation deficient complex 4) can be leveraged for targeted protein degradation using a noncovalent small molecule. We design and synthesize GID4-based PROTACs, exemplified by NEP162, which can eliminate endogenous BRD4 in a GID4- and ubiquitin–proteasome system-dependent manner. NEP162 exhibits antiproliferative activity and inhibits tumor growth in a xenograft model, hinting toward potential anticancer applications. We further present the crystal structures of GID4–PROTAC–BRD4 ternary complexes in three distinct states, unveiling plastic interactions between GID4 and BRD4. These structural insights, combined with in vitro and in vivo data, decipher the molecular basis by which the hereby developed PROTACs recruit BRD4 to GID4 for targeted degradation and expand our arsenal of PROTAC-exploitable E3 ligases.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880584","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

Cholesterol finds its pocket in LYCHOS 胆固醇在LYCHOS中找到了自己的口袋

Nature structural & molecular biology Pub Date : 2025-04-28 DOI: 10.1038/s41594-025-01551-3

Hijai R. Shin, Roberto Zoncu

引用次数: 0

Recruitment of Atg1 to the phagophore by Atg8 orchestrates autophagy machineries Atg8将Atg1招募到噬细胞中，协调了自噬机制

Nature structural & molecular biology Pub Date : 2025-04-28 DOI: 10.1038/s41594-025-01546-0

Jing-Zhen Song, Hui Li, Haiyan Yang, Rui Liu, Wenting Zhang, Tianlong He, Meng-Xi Xie, Chen Chen, Li Cui, Shian Wu, Yueguang Rong, Li-Feng Pan, Jing Zhu, Qingqiu Gong, Juan Wang, Zhao Qin, Zhiping Xie

{"title":"Recruitment of Atg1 to the phagophore by Atg8 orchestrates autophagy machineries","authors":"Jing-Zhen Song, Hui Li, Haiyan Yang, Rui Liu, Wenting Zhang, Tianlong He, Meng-Xi Xie, Chen Chen, Li Cui, Shian Wu, Yueguang Rong, Li-Feng Pan, Jing Zhu, Qingqiu Gong, Juan Wang, Zhao Qin, Zhiping Xie","doi":"10.1038/s41594-025-01546-0","DOIUrl":"https://doi.org/10.1038/s41594-025-01546-0","url":null,"abstract":"Autophagy-related (Atg) proteins catalyze autophagosome formation at the phagophore assembly site (PAS). The assembly of Atg proteins at the PAS follows a semihierarchical order, in which Atg8 is thought to be quite downstream but still able to control the size of autophagosomes. Yet, how Atg8 coordinates multiple branches of autophagy machinery to regulate autophagosomal size is not clear. Here, we show that, in yeast, Atg8 positively regulates the autophagy-specific phosphatidylinositol 3-OH kinase complex and the retrograde trafficking of Atg9 vesicles through interaction with Atg1. Mechanistically, Atg8 does not enhance the kinase activity of Atg1; instead, it recruits Atg1 to the surface of the phagophore likely to orient Atg1’s activity toward select substrates, leading to efficient phagophore expansion. Artificial tethering of Atg1 kinase domains to Atg8s enhanced autophagy in yeast, human and plant cells and improved muscle performance in worms. We propose that Atg8-mediated relocation of Atg1 from the PAS scaffold to the phagophore is a critical step in positive autophagy regulation.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880591","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 mechanochemical cycle of reactive full-length human dynein 1 反应性全长人动力蛋白的机械化学循环

Nature structural & molecular biology Pub Date : 2025-04-22 DOI: 10.1038/s41594-025-01543-3

Pengxin Chai, Jun Yang, Indigo C. Geohring, Steven M. Markus, Yue Wang, Kai Zhang

{"title":"The mechanochemical cycle of reactive full-length human dynein 1","authors":"Pengxin Chai, Jun Yang, Indigo C. Geohring, Steven M. Markus, Yue Wang, Kai Zhang","doi":"10.1038/s41594-025-01543-3","DOIUrl":"https://doi.org/10.1038/s41594-025-01543-3","url":null,"abstract":"Dynein-driven cargo transport has a pivotal role in diverse cellular activities, central to which is dynein’s mechanochemical cycle. Here, we performed a systematic cryo-electron microscopic investigation of the conformational landscape of full-length human dynein 1 in reaction, in various nucleotide conditions, on and off microtubules. Our approach reveals over 40 high-resolution structures, categorized into eight states, providing a dynamic and comprehensive view of dynein throughout its mechanochemical cycle. The described intermediate states reveal mechanistic insights into dynein function, including a ‘backdoor’ phosphate release model that coordinates linker straightening, how microtubule binding enhances adenosine triphosphatase activity through a two-way communication mechanism and the crosstalk mechanism between AAA1 and the regulatory AAA3 site. Our findings also lead to a revised model for the force-generating powerstroke and reveal means by which dynein exhibits unidirectional stepping. These results improve our understanding of dynein and provide a more complete model of its mechanochemical cycle.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857786","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

Cryo-EM structures of PP2A:B55 with p107 and Eya3 define substrate recruitment PP2A:B55与p107和Eya3的Cryo-EM结构定义了底物募集

Nature structural & molecular biology Pub Date : 2025-04-17 DOI: 10.1038/s41594-025-01535-3

Sathish K. R. Padi, Rachel J. Godek, Wolfgang Peti, Rebecca Page

{"title":"Cryo-EM structures of PP2A:B55 with p107 and Eya3 define substrate recruitment","authors":"Sathish K. R. Padi, Rachel J. Godek, Wolfgang Peti, Rebecca Page","doi":"10.1038/s41594-025-01535-3","DOIUrl":"https://doi.org/10.1038/s41594-025-01535-3","url":null,"abstract":"Phosphoprotein phosphatases (PPPs) achieve specificity by binding substrates and regulators using PPP-specific short motifs. Protein phosphatase 2A (PP2A) is a highly conserved phosphatase that regulates cell signaling and is a tumor suppressor. Here, we use cryo-electron microscopy and nuclear magnetic resonance (NMR) spectroscopy to investigate the mechanisms of human p107 substrate and Eya3 regulator recruitment to the PP2A:B55 holoenzyme. We show that, while they associate with B55 using a common set of interaction pockets, the mechanism of substrate and regulator binding differs and is distinct from that observed for PP2A:B56 and other PPPs. We also identify the core B55 recruitment motif in Eya3 proteins, a sequence conserved amongst the Eya family. Lastly, using NMR-based dephosphorylation assays, we demonstrate how B55 recruitment directs PP2A:B55 fidelity through the selective dephosphorylation of specific phosphosites. As PP2A:B55 orchestrates mitosis and DNA damage repair, these data provide a roadmap for pursuing new avenues to therapeutically target this complex by individually blocking a subset of regulators that use different B55 interaction sites.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"108 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841320","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 subcortical maternal complex safeguards mouse oocyte-to-embryo transition by preventing nuclear entry of SPIN1 皮层下母体复合物通过阻止SPIN1的核进入来保护小鼠卵细胞向胚胎的转变

Nature structural & molecular biology Pub Date : 2025-04-17 DOI: 10.1038/s41594-025-01538-0

Chengpeng Xu, Dandan Qin, Xukun Lu, Qianqian Qi, Yu Wu, Qizhi Wang, Zhuo Han, Xiaoqing Nie, Yongmei Jiang, Dong Deng, Wei Xie, Zheng Gao, Lei Li

{"title":"The subcortical maternal complex safeguards mouse oocyte-to-embryo transition by preventing nuclear entry of SPIN1","authors":"Chengpeng Xu, Dandan Qin, Xukun Lu, Qianqian Qi, Yu Wu, Qizhi Wang, Zhuo Han, Xiaoqing Nie, Yongmei Jiang, Dong Deng, Wei Xie, Zheng Gao, Lei Li","doi":"10.1038/s41594-025-01538-0","DOIUrl":"https://doi.org/10.1038/s41594-025-01538-0","url":null,"abstract":"How cytoplasmic regulators control nuclear events in mammalian oocytes and early embryos remains largely enigmatic. We previously identified a subcortical maternal complex (SCMC) that specifically resides in the cytoplasm of mammalian oocytes and early embryos but is also involved in nuclear events. Nevertheless, how the cytoplasmic SCMC exerts its role in nuclear processes remains unknown. In this study, we unveil SPIN1, a histone methylation reader, as a novel member of the SCMC. The SCMC component FILIA tightly regulates the expression and cytoplasmic localization of SPIN1 through direct interaction. When the expression of FILIA is decreased because of genetic mutations of SCMC genes, SPIN1 expression is dramatically reduced but the residual SPIN1 translocates into the nucleus. The abnormal nuclear presence of SPIN1 impairs H3K4me3 reprogramming, zygotic genome activation and physiological embryonic development. Inhibiting the interaction between SPIN1 and H3K4me3 partially rescues the abnormal phenotype in FILIA-null embryos. Mechanistically, SPIN1 partially perturbs the demethylation process by competing with KDM5B for binding to H3K4me3. Collectively, our work highlights the complexity of the mammalian SCMC and oocyte-to-embryo transition, revealing an intricate regulatory mechanism that facilitates the smooth progression of this process.","PeriodicalId":18822,"journal":{"name":"Nature structural & molecular biology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841388","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