The EMBO Journal最新文献_第2页

Elucidating the protein interaction network of one of the largest icosahedral capsids in the virosphere. 阐明病毒圈中最大的二十面体衣壳之一的蛋白质相互作用网络。

The EMBO Journal Pub Date : 2026-04-10 DOI: 10.1038/s44318-026-00770-8

Hela Safi,Alain Schmitt,Alwena Tollec,Lucid Belmudes,Agathe M G Colmant,Olivier Poirot,Sebastien Santini,Matthieu Legendre,Yohann Couté,Hugo Bisio,Chantal Abergel

{"title":"Elucidating the protein interaction network of one of the largest icosahedral capsids in the virosphere.","authors":"Hela Safi,Alain Schmitt,Alwena Tollec,Lucid Belmudes,Agathe M G Colmant,Olivier Poirot,Sebastien Santini,Matthieu Legendre,Yohann Couté,Hugo Bisio,Chantal Abergel","doi":"10.1038/s44318-026-00770-8","DOIUrl":"https://doi.org/10.1038/s44318-026-00770-8","url":null,"abstract":"Giant viruses challenge traditional boundaries of virology with their large particle sizes, complex genomes, and unique replication strategies. Yet, despite its 750 nm diameter and incorporation of dozens of proteins, the mimivirus virion retains an icosahedral symmetry, a trait often associated with smaller viruses. The functional roles and interactions of most proteins composing such complex icosahedral particles remain elusive. Here, we dissect the spatial and functional organization of mimivirus morphogenesis by integrating bioinformatics, genetics, and interactomics. We performed protein clustering using a structure-informed approach, integrating AlphaFold models with sequence information, to classify and functionally annotate the orphan-protein-rich mimivirus proteome. To map the protein-protein interaction network during morphogenesis, we employed endogenous tagging and co-immunoprecipitation coupled to mass spectrometry. This strategy revealed distinct interaction modules associated with the virion membrane, nucleoid, and viral factory compartments. Comparative analyses with other icosahedral and non-icosahedral giant viruses uncovered conserved assembly nodes and virion-shape-specific adaptations. Our findings shed light on the global organization of mimivirus virion biogenesis and highlight the evolutionary plasticity of viral morphogenetic networks within the Nucleocytoviricota.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147648914","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 H3K36me3 methyltransferase SETD2 contributes to PAF1C interactions with RNA Pol II and is required for neuronal differentiation. H3K36me3甲基转移酶SETD2有助于PAF1C与RNA Pol II的相互作用，并且是神经元分化所必需的。

The EMBO Journal Pub Date : 2026-04-10 DOI: 10.1038/s44318-026-00768-2

Christina Ambrosi,Ramon Pfaendler,Kristeli Eleftheriou,Stefan Butz,Davide Recchia,Xue Bao,Richard Cardoso da Silva,Niklas Kupfer,Ilse M Lagerwaard,Hanneke Vlaming,Nina Schmolka,Vivek Bhardwaj,Tuncay Baubec

引用次数: 0

SenSet defines cell-type specific senescence signatures in the aged human lung. SenSet定义了老年人肺中细胞类型特异性衰老特征。

The EMBO Journal Pub Date : 2026-04-10 DOI: 10.1038/s44318-026-00762-8

Euxhen Hasanaj,Delphine Beaulieu,Cankun Wang,Qianjiang Hu,Lorena Rosas,Marta Bueno,John C Sembrat,Ricardo H Pineda,Maria Camila Melo-Narvaez,Nayra Cardenes,Zhao Yanwu,Zhang Yingze,Robert Lafyatis,Alison Morris,Ana Mora,Mauricio Rojas,Dongmei Li,Irfan Rahman,Gloria S Pryhuber,Mareike Lehmann,Jonathan Alder,Aditi Gurkar,Toren Finkel,Qin Ma,Jose Lugo-Martinez,Barnabás Póczos,Ziv Bar-Joseph,Oliver Eickelberg,Melanie Königshoff

{"title":"SenSet defines cell-type specific senescence signatures in the aged human lung.","authors":"Euxhen Hasanaj,Delphine Beaulieu,Cankun Wang,Qianjiang Hu,Lorena Rosas,Marta Bueno,John C Sembrat,Ricardo H Pineda,Maria Camila Melo-Narvaez,Nayra Cardenes,Zhao Yanwu,Zhang Yingze,Robert Lafyatis,Alison Morris,Ana Mora,Mauricio Rojas,Dongmei Li,Irfan Rahman,Gloria S Pryhuber,Mareike Lehmann,Jonathan Alder,Aditi Gurkar,Toren Finkel,Qin Ma,Jose Lugo-Martinez,Barnabás Póczos,Ziv Bar-Joseph,Oliver Eickelberg,Melanie Königshoff","doi":"10.1038/s44318-026-00762-8","DOIUrl":"https://doi.org/10.1038/s44318-026-00762-8","url":null,"abstract":"Cellular senescence is defined as an irreversible growth arrest observed when cells are exposed to a variety of stressors, including DNA damage, oxidative stress, or nutrient deprivation. Although senescence is a well-established driver of aging and age-related diseases, it is a highly heterogeneous process with significant variations across organisms, tissues, and cell types. The relatively low abundance of senescent cells in healthy aged tissues poses a major challenge to the longitudinal study of senescence in specific organs, including the human lung. To overcome this limitation, we developed a positive-unlabeled learning framework to generate a comprehensive list of senescence marker genes in human lungs (termed SenSet) using the largest publicly available single-cell lung dataset, the Human Lung Cell Atlas (HLCA). We validated SenSet in a highly complex ex vivo human 3D lung tissue culture model subjected to the senescence inducers bleomycin, doxorubicin, or irradiation, and established its sensitivity and accuracy in characterizing senescence. Using SenSet, we identified and validated cell-type-specific senescence signatures in distinct lung cell populations upon aging and environmental exposure. Our study provides a comprehensive analysis of senescent cells in the healthy aging lung, presenting fundamental implications for our understanding of major lung diseases, including cancer, fibrosis, chronic obstructive pulmonary disease, or asthma.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147648877","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

Global stabilization of the transcriptome in mitotic cells. 有丝分裂细胞中转录组的全局稳定。

The EMBO Journal Pub Date : 2026-04-09 DOI: 10.1038/s44318-026-00765-5

Ekaterina Khalizeva,Arash Latifkar,Kehui Xiang,David P Bartel,Jimmy Ly,Iain M Cheeseman

{"title":"Global stabilization of the transcriptome in mitotic cells.","authors":"Ekaterina Khalizeva,Arash Latifkar,Kehui Xiang,David P Bartel,Jimmy Ly,Iain M Cheeseman","doi":"10.1038/s44318-026-00765-5","DOIUrl":"https://doi.org/10.1038/s44318-026-00765-5","url":null,"abstract":"In the presence of cell division errors, mammalian cells can pause in mitosis for tens of hours with little to no transcription, while still requiring continued translation for viability. These unique aspects of mitosis require substantial adaptations to gene expression. During interphase, homeostatic control of mRNA levels involves a constant balance of transcription and degradation, with a median mRNA half-life of ~2-4 h. If such short half-lives persisted in mitosis, cells would be expected to rapidly deplete their transcriptome without new transcription. Here, we report that the transcriptome is globally stabilized during prolonged mitotic delays. Median mRNA half-lives are increased >4-fold during mitotic arrest compared to interphase, buffering mRNA levels in the absence of new synthesis. Moreover, poly(A) tail-length profiles change during mitotic arrest, strongly suggesting a partial mitotic repression of deadenylation. In contrast, siRNA-directed mRNA degradation machinery remains active. We further show that mitotic mRNA stabilization depends on PABPC1&4. Depletion of PABPC1&4 during mitotic arrest reduces mRNA stability and disrupts the cells' ability to maintain arrest, highlighting the critical physiological role of mitotic transcriptome buffering.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"21 5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147641626","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

Global analysis of cancer cell responses to USP9X inhibition. 肿瘤细胞对USP9X抑制反应的全局分析。

The EMBO Journal Pub Date : 2026-04-07 DOI: 10.1038/s44318-026-00742-y

Philipp Schenk,Shane M Devine,Simon A Cobbold,Niall D Geoghegan,Elizabeth L Kyran,Ching-Seng Ang,Jack A Alexandrovics,Dale J Calleja,Dylan H Multari,Vineet Vaibhav,Bernadine G C Lu,Theresa A Klemm,Laura F Dagley,Kym N Lowes,Nicholas A Williamson,Pieter J A Eichhorn,Ashley P Ng,Rebecca Feltham,David Komander

{"title":"Global analysis of cancer cell responses to USP9X inhibition.","authors":"Philipp Schenk,Shane M Devine,Simon A Cobbold,Niall D Geoghegan,Elizabeth L Kyran,Ching-Seng Ang,Jack A Alexandrovics,Dale J Calleja,Dylan H Multari,Vineet Vaibhav,Bernadine G C Lu,Theresa A Klemm,Laura F Dagley,Kym N Lowes,Nicholas A Williamson,Pieter J A Eichhorn,Ashley P Ng,Rebecca Feltham,David Komander","doi":"10.1038/s44318-026-00742-y","DOIUrl":"https://doi.org/10.1038/s44318-026-00742-y","url":null,"abstract":"The ubiquitin-specific protease (USP) USP9X is a human deubiquitinase (DUB) with a large number of described targets and cellular roles. In cancer, USP9X is found as an oncogene or as a tumour suppressor depending on context, and its utility as a target for cancer therapy remains unclear. We here describe WEHI-092, a piperazine-based USP9X-specific small-molecule inhibitor, which binds to a unique region in the USP9X Fingers-subdomain, distinct from known DUB-inhibitor binding sites. Using proteomics and ubiquitinomics, we show that USP9X targets distinct substrates compared to USP7, yet the substrate profile of USP9X varies significantly across cancer cell lines. We reveal a core set of 17 proteins commonly regulated by USP9X in most cell lines, which we consider as proximal biomarkers for USP9X inhibition. Consistent with proteomics, we show in unrelated cell lines that WEHI-092 treatment arrests the cell cycle in metaphase without inducing cell death. This explains growth suppression in long-term clonogenic assays in most cancer cell lines, and positions USP9X inhibitors as a new class of selective mitotic poisons.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147630371","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 spontaneous termination mechanism of RNA polymerase V shapes the DNA methylation landscape in plants. RNA聚合酶V的自发终止机制塑造了植物DNA甲基化景观。

The EMBO Journal Pub Date : 2026-04-02 DOI: 10.1038/s44318-026-00763-7

Guohui Xie,Xuan Du,Yifang Tan,Yuxing Zhou,Cheng Chi,Sixian Zhou,Colette L Picard,Songge Chai,Lei Wu,Danling Zhu,Jun Zhao,Yan Xue,Sisi Li,Steven E Jacobsen,Zhe Wu,Jiamu Du

{"title":"A spontaneous termination mechanism of RNA polymerase V shapes the DNA methylation landscape in plants.","authors":"Guohui Xie,Xuan Du,Yifang Tan,Yuxing Zhou,Cheng Chi,Sixian Zhou,Colette L Picard,Songge Chai,Lei Wu,Danling Zhu,Jun Zhao,Yan Xue,Sisi Li,Steven E Jacobsen,Zhe Wu,Jiamu Du","doi":"10.1038/s44318-026-00763-7","DOIUrl":"https://doi.org/10.1038/s44318-026-00763-7","url":null,"abstract":"DNA methylation plays critical roles in eukaryotic gene silencing, genome imprinting, viral defense, and suppression of transposable elements. In plants, RNA Polymerase V (Pol V)-generated non-coding RNA guides DNA methylation through the RNA-directed DNA methylation (RdDM) pathway; however, how these RNAs are selected is unknown. Here, we show that the 3'-ends of Pol V transcripts are enriched at A-rich template DNA (A-rich-DNAT). Arabidopsis RdDM regions possess AT-rich boundaries genome-wide, suggesting that Pol V likely terminates at A-rich-DNAT, which subsequently defines the DNA methylation landscape in plants. A-rich-DNAT successfully stops Pol V transcription in vitro. Structural snapshots of Pol V transcribing A-rich-DNAT show that accumulation of unstable rU:dA pairs in the RNA-DNA hybrid promotes transcription bubble collapse and spontaneous transcription termination. These findings identify an intrinsic Pol V termination signal that shapes genomic DNA methylation patterning in plants and reveals a common mechanism for spontaneous transcription termination.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147599524","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 leader-repeat hairpin blocks extraneous CRISPR RNA production in diverse CRISPR-Cas13 systems. 在不同的CRISPR- cas13系统中，先导重复发夹阻断了外来CRISPR RNA的产生。

The EMBO Journal Pub Date : 2026-04-02 DOI: 10.1038/s44318-026-00769-1

Angela Migur,Maximilian Feussner,Chunyu Liao,Omer S Alkhnbashi,Adrien Chauvier,Nils G Walter,Rolf Backofen,Zasha Weinberg,Chase L Beisel

{"title":"A leader-repeat hairpin blocks extraneous CRISPR RNA production in diverse CRISPR-Cas13 systems.","authors":"Angela Migur,Maximilian Feussner,Chunyu Liao,Omer S Alkhnbashi,Adrien Chauvier,Nils G Walter,Rolf Backofen,Zasha Weinberg,Chase L Beisel","doi":"10.1038/s44318-026-00769-1","DOIUrl":"https://doi.org/10.1038/s44318-026-00769-1","url":null,"abstract":"CRISPR RNAs (crRNAs) guide recognition and targeting of intracellular invaders as part of adaptive immunity by CRISPR-Cas systems. crRNAs are transcribed from CRISPR arrays of conserved repeats interlaced with invader-derived spacers. While crRNA production is essential for immunity, its optimization for defense remains poorly understood. Here, we show that, in diverse RNA-targeting type VI CRISPR-Cas systems, the leader RNA encoded upstream of the CRISPR array prevents formation of an invader-independent extraneous crRNA (ecrRNA) by blocking processing of the first repeat. Using the VI-B2 system from Porphyromonas gingivalis as a model, we demonstrate that the leader RNA and first repeat form a conserved inhibitory hairpin that precludes binding and processing by the system's Cas13b nuclease. Disrupting this hairpin enables ecrRNA production, which in turn can deplete invader-derived crRNAs and reduce Cas13b-mediated phage defense. Structure prediction indicates that these leader-repeat hairpins are widespread across diverse type VI subtypes, highlighting a conserved regulatory mechanism. Our findings reveal how a prevalent branch of CRISPR-Cas systems suppresses ecrRNA formation to promote RNA-guided immunity.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147599502","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

Orphan nuclear receptors recruit TRIM28 to promote telomeric H3K9me3 for the ALT pathway. 孤儿核受体募集TRIM28促进ALT通路的端粒H3K9me3。

The EMBO Journal Pub Date : 2026-03-31 DOI: 10.1038/s44318-026-00760-w

Chia-Tsen Tsai,Venus Marie Gaela,Hsuan-Yu Hsia,Yu-Chen Huang,Yi-Ling Shen,Liuh-Yow Chen

{"title":"Orphan nuclear receptors recruit TRIM28 to promote telomeric H3K9me3 for the ALT pathway.","authors":"Chia-Tsen Tsai,Venus Marie Gaela,Hsuan-Yu Hsia,Yu-Chen Huang,Yi-Ling Shen,Liuh-Yow Chen","doi":"10.1038/s44318-026-00760-w","DOIUrl":"https://doi.org/10.1038/s44318-026-00760-w","url":null,"abstract":"Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism deployed in embryonic stem cells and cancer cells. High levels of the heterochromatin mark H3 lysine 9 trimethylation (H3K9me3) at telomeres are critical for ALT, but how this is achieved remains unclear. Telomeric association of orphan nuclear receptors (NRs)-such as COUP-TF1, COUP-TF2, TR2, and TR4-has been shown previously to facilitate ALT activation. Here, we show that orphan NRs regulate telomeric H3K9me3 through TRIM28, a corepressor of ZNF transcription factors, to promote ALT. We report that H3K9me3 is induced by telomeric association of orphan NRs in cultured human fibroblast and ALT cancer cell lines. Moreover, TRIM28 is required for the orphan-NR-induced H3K9 methylation and ALT phenotypes. Importantly, physical interaction of TRIM28 with orphan NRs induces telomeric localization of TRIM28. A TRIM28 variant defective in orphan-NR interaction fails to localize to telomeres and is unable to promote H3K9me3 and ALT phenotypes. These findings indicate that telomeric orphan NRs recruit TRIM28 for telomeric H3K9me3 and ALT activation, emphasizing the role of chromatin structure in ALT activation.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583809","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

Mechanistic basis for selective Csm6-2 activation by cyclic penta-adenylate in a type III CRISPR-Cas system. III型CRISPR-Cas系统中环五腺苷酸选择性激活Csm6-2的机制基础。

The EMBO Journal Pub Date : 2026-03-31 DOI: 10.1038/s44318-026-00767-3

Ruyi Shi,Mengquan Yang,Yusong Liu,Haishan Gao,Zhonghui Lin

{"title":"Mechanistic basis for selective Csm6-2 activation by cyclic penta-adenylate in a type III CRISPR-Cas system.","authors":"Ruyi Shi,Mengquan Yang,Yusong Liu,Haishan Gao,Zhonghui Lin","doi":"10.1038/s44318-026-00767-3","DOIUrl":"https://doi.org/10.1038/s44318-026-00767-3","url":null,"abstract":"Type III CRISPR systems generate cyclic oligoadenylate (cOA, 3 to 6 AMPs) messengers upon detecting viral RNA, activating downstream effectors to defend against viral infection. Although cOA-activated effectors have been extensively characterized, the effectors specific to cA5-one of the most abundant cOA species produced during phage infection-have remained unexplored. Here, we report that the CRISPR ribonuclease Csm6 (Csm6-2) from Actinomyces procaprae selectively employs cA5 as its activator. Csm6-2 utilizes its HEPN domain, rather than the CARF domain, to mediate self-limiting cleavage of cOA activators. Cryo-EM structural analyses reveal that Csm6-2 functions as a homotetramer, and disruption of tetramer formation significantly reduces its ribonuclease activity. Although cA6 and cA5 bind Csm6-2 with comparable affinity, only cA5 induces CARF domain closure, stabilizes the tetramer, and remodels the active site in the HEPN domain. In contrast, the sixth AMP of cA6 imposes significant steric hindrance on CARF domain movement, preventing its closure and subsequent allosteric activation. These findings expand our understanding of the cOA signaling diversity and specific cOA recognition mechanisms in type III CRISPR immunity.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147583816","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 insight into ligand binding and activation of the orphan GPCR Mas1. 孤儿GPCR Mas1配体结合和激活的结构洞察。

The EMBO Journal Pub Date : 2026-03-30 DOI: 10.1038/s44318-026-00764-6

Yumu Zhang,Qiuying Wang,Heng Liu,Hong Shan,Yimin Gu,Jiaqi Yang,Yuan Gao,Kai Wu,Dehua Yang,H Eric Xu

{"title":"Structural insight into ligand binding and activation of the orphan GPCR Mas1.","authors":"Yumu Zhang,Qiuying Wang,Heng Liu,Hong Shan,Yimin Gu,Jiaqi Yang,Yuan Gao,Kai Wu,Dehua Yang,H Eric Xu","doi":"10.1038/s44318-026-00764-6","DOIUrl":"https://doi.org/10.1038/s44318-026-00764-6","url":null,"abstract":"The Mas1 receptor, an orphan class A G-protein-coupled receptor (GPCR), plays pivotal roles in cardiovascular and anti-inflammatory regulation. Despite its therapeutic relevance, the structural mechanisms underlying Mas1 ligand binding and activation remain poorly understood. Here, we report cryo-EM structures of Mas1 bound to two chemically distinct agonists-neuropeptide FF (NPFF) and synthetic small-molecule AR234958-captured in complex with inhibitory G proteins. These structures reveal a conserved orthosteric binding pocket accommodating both ligands through shared hydrophobic interactions. Unlike many other class A GPCRs that rely on direct W6.48 toggle switch engagement, Mas1 adopts a non-canonical activation strategy driven by a ligand-induced hydrophobic compression plane involving residues Y2486.55, L872.60, I842.57, and L2667.39 at the bottom of the ligand binding pocket. This mechanism transmits mechanical tension to promote TM6 displacement and G protein coupling. Functional mutagenesis validates this model, identifying two transmembrane helix 6 (TM6) residues, M2446.51 and F2376.44, as critical molecular switches. Comparative analyses of Mas1-related receptors, MRGPRX1-X4, reveal conserved features and mechanistic divergence within this subfamily. These findings provide a structural framework for understanding Mas1 pharmacology and rational design of selective therapeutics.","PeriodicalId":501009,"journal":{"name":"The EMBO Journal","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147578173","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