Cell ResearchPub Date : 2025-04-21DOI: 10.1038/s41422-025-01121-8
Xianglin Huang, Brian E. Krumm, Bryan L. Roth
{"title":"Orchestrating NTSR1 signaling from the interface","authors":"Xianglin Huang, Brian E. Krumm, Bryan L. Roth","doi":"10.1038/s41422-025-01121-8","DOIUrl":"10.1038/s41422-025-01121-8","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 6","pages":"395-396"},"PeriodicalIF":25.9,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01121-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell ResearchPub Date : 2025-04-16DOI: 10.1038/s41422-025-01113-8
Heng Liu, Shimeng Guo, Antao Dai, Peiyu Xu, Xin Li, Sijie Huang, Xinheng He, Kai Wu, Xinyue Zhang, Dehua Yang, Xin Xie, H. Eric Xu
{"title":"Author Correction: Structural and functional evidence that GPR30 is not a direct estrogen receptor","authors":"Heng Liu, Shimeng Guo, Antao Dai, Peiyu Xu, Xin Li, Sijie Huang, Xinheng He, Kai Wu, Xinyue Zhang, Dehua Yang, Xin Xie, H. Eric Xu","doi":"10.1038/s41422-025-01113-8","DOIUrl":"10.1038/s41422-025-01113-8","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 7","pages":"532-534"},"PeriodicalIF":25.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell ResearchPub Date : 2025-04-16DOI: 10.1038/s41422-025-01114-7
Zhenzhen Li, Qikui Xu, Yan Zhang, Jing Zhong, Tianxiang Zhang, Junchao Xue, Shuxian Liu, Haishan Gao, Z. Z. Zhao Zhang, Jianping Wu, En-Zhi Shen
{"title":"Mechanistic insights into RNA cleavage by human Argonaute2–siRNA complex","authors":"Zhenzhen Li, Qikui Xu, Yan Zhang, Jing Zhong, Tianxiang Zhang, Junchao Xue, Shuxian Liu, Haishan Gao, Z. Z. Zhao Zhang, Jianping Wu, En-Zhi Shen","doi":"10.1038/s41422-025-01114-7","DOIUrl":"10.1038/s41422-025-01114-7","url":null,"abstract":"In animals, AGO-clade Argonaute proteins utilize small interfering RNAs (siRNAs) as guides to recognize target with complete complementarity, resulting in target RNA cleavage that is a critical step for target silencing. These proteins feature a constricted nucleic acid-binding channel that limits base pairing between the guide and target beyond the seed region. How the AGO–siRNA complexes overcome this structural limitation and achieve efficient target cleavage remains unclear. We performed cryo-electron microscopy of human AGO–siRNA complexes bound to target RNAs of increasing lengths to examine the conformational changes associated with target recognition and cleavage. Initially, conformational transition propagates from the opening of the PAZ domain and extends through a repositioning of the PIWI–L1–N domain toward the binding channel, facilitating the capture of siRNA–target duplex. Subsequent extension of base pairing drives the downward movement of the PIWI–L1–N domain to enable catalytic activation. Finally, further base pairing toward the 3′ end of siRNA destabilizes the PAZ–N domain, resulting in a “uni-lobed” architecture, which might facilitate the multi-turnover action of the AGO–siRNA enzyme complex. In contrast to PIWI-clade Argonautes, the “uni-lobed” structure of the AGO complex makes multiple contacts with the target in the central region of the siRNA–target duplex, positioning it within the catalytic site. Our findings shed light on the stepwise mechanisms by which the AGO–siRNA complex executes target RNA cleavage and offer insights into the distinct operational modalities of AGO and PIWI proteins in achieving such cleavage.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 6","pages":"453-464"},"PeriodicalIF":25.9,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836746","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}
Cell ResearchPub Date : 2025-04-15DOI: 10.1038/s41422-025-01119-2
Michal Schwartz
{"title":"Why resident microglial-like cells were missed in the peripheral nervous system.","authors":"Michal Schwartz","doi":"10.1038/s41422-025-01119-2","DOIUrl":"https://doi.org/10.1038/s41422-025-01119-2","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":" ","pages":""},"PeriodicalIF":28.1,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970444","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}
Cell ResearchPub Date : 2025-04-14DOI: 10.1038/s41422-025-01117-4
Manuel Beltrán-Visiedo, Rebecca M. Shulman, Lorenzo Galluzzi
{"title":"Selective CDK4 inhibition holds promise for breast cancer","authors":"Manuel Beltrán-Visiedo, Rebecca M. Shulman, Lorenzo Galluzzi","doi":"10.1038/s41422-025-01117-4","DOIUrl":"https://doi.org/10.1038/s41422-025-01117-4","url":null,"abstract":"<p><b>Although CDK4/6 inhibitors have revolutionized the management of patients with locally advanced/metastatic HR</b><sup><b>+</b></sup><b>HER2</b><sup><i>−</i></sup> <b>breast cancer, hematological side effects, notably neutropenia, have been challenging to circumvent. A highly selective CDK4 inhibitor has recently been shown to cause limited hematological toxicity in preclinical breast cancer models, hence enabling dose escalation in support of superior tumor control</b>.</p>","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"108 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827135","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}
Cell ResearchPub Date : 2025-04-14DOI: 10.1038/s41422-025-01116-5
Thomas C. T. Michaels, Anton Wutz
{"title":"Phase separation paints Xi with Xist","authors":"Thomas C. T. Michaels, Anton Wutz","doi":"10.1038/s41422-025-01116-5","DOIUrl":"10.1038/s41422-025-01116-5","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 9","pages":"625-626"},"PeriodicalIF":25.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01116-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143827375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structural basis of stepwise proton sensing-mediated GPCR activation","authors":"Xiaolei Yue, Li Peng, Shenhui Liu, Bingjie Zhang, Xiaodan Zhang, Hao Chang, Yuan Pei, Xiaoting Li, Junlin Liu, Wenqing Shui, Lijie Wu, Huji Xu, Zhi-Jie Liu, Tian Hua","doi":"10.1038/s41422-025-01092-w","DOIUrl":"10.1038/s41422-025-01092-w","url":null,"abstract":"The regulation of pH homeostasis is crucial in many biological processes vital for survival, growth, and function of life. The pH-sensing G protein-coupled receptors (GPCRs), including GPR4, GPR65 and GPR68, play a pivotal role in detecting changes in extracellular proton concentrations, impacting both physiological and pathological states. However, comprehensive understanding of the proton sensing mechanism is still elusive. Here, we determined the cryo-electron microscopy structures of GPR4 and GPR65 in various activation states across different pH levels, coupled with Gs, Gq or G13 proteins, as well as a small molecule NE52-QQ57-bound inactive GPR4 structure. These structures reveal the dynamic nature of the extracellular loop 2 and its signature conformations in different receptor states, and disclose the proton sensing mechanism mediated by networks of extracellular histidine and carboxylic acid residues. Notably, we unexpectedly captured partially active intermediate states of both GPR4–Gs and GPR4–Gq complexes, and identified a unique allosteric binding site for NE52-QQ57 in GPR4. By integrating prior investigations with our structural analysis and mutagenesis data, we propose a detailed atomic model for stepwise proton sensation and GPCR activation. These insights may pave the way for the development of selective ligands and targeted therapeutic interventions for pH sensing-relevant diseases.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"35 6","pages":"423-436"},"PeriodicalIF":25.9,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}