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The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity ALS 药物利鲁唑与 SARS-CoV-2 核头状蛋白的 C 端结构域结合并具有抗病毒活性

IF 5.7 2区生物学

Structure Pub Date : 2024-11-13 DOI: 10.1016/j.str.2024.10.025

María Ángeles Márquez-Moñino, Clara M. Santiveri, Patricia de León, Sergio Camero, Ramón Campos-Olivas, M. Ángeles Jiménez, Margarita Sáiz, Beatriz González, José Manuel Pérez-Cañadillas

{"title":"The ALS drug riluzole binds to the C-terminal domain of SARS-CoV-2 nucleocapsid protein and has antiviral activity","authors":"María Ángeles Márquez-Moñino, Clara M. Santiveri, Patricia de León, Sergio Camero, Ramón Campos-Olivas, M. Ángeles Jiménez, Margarita Sáiz, Beatriz González, José Manuel Pérez-Cañadillas","doi":"10.1016/j.str.2024.10.025","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.025","url":null,"abstract":"Nucleoproteins (N) play an essential role in virus assembly and are less prone to mutation than other viral structural proteins, making them attractive targets for drug discovery. Using an NMR fragment-based drug discovery approach, we identified the 1,3-benzothiazol-2-amine (BZT) group as a scaffold to develop potential antivirals for SARS-CoV-2 nucleocapsid (N) protein. A thorough characterization of BZT derivatives using NMR, X-ray crystallography, antiviral activity assays, and intrinsic fluorescence measurements revealed their binding in the C-terminal domain (CTD) domain of the N protein, to residues Arg 259, Trp 330, and Lys 338, coinciding with the nucleotide binding site. Our most effective compound exhibits a slightly better affinity than GTP and the ALS drug riluzole, also identified during the screening, and displays notable viral inhibition activity. A virtual screening of 218 BZT-based compounds revealed a potential extended binding site that could be exploited for the future development of new SARS-CoV-2 antivirals.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"41 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural and biochemical insights into the mechanism of the anti-CRISPR protein AcrIE3 从结构和生化角度揭示抗 CRISPR 蛋白 AcrIE3 的作用机制

IF 5.7 2区生物学

Structure Pub Date : 2024-11-13 DOI: 10.1016/j.str.2024.10.024

Jasung Koo, Gyujin Lee, Changkon Park, Hyejin Oh, Sung-Hyun Hong, Jeong-Yong Suh, Euiyoung Bae

引用次数: 0

Deciphering the molecular mechanism underlying morphology transition in two-component DNA-protein cophase separation 破译双组分 DNA 蛋白共相分离中形态转变的分子机制

IF 5.7 2区生物学

Structure Pub Date : 2024-11-13 DOI: 10.1016/j.str.2024.10.026

Cheng Li, Yunqiang Bian, Yiting Tang, Lingyu Meng, Peipei Yin, Ye Hong, Jun Cheng, Yuchen Li, Jie Lin, Chao Tang, Chunlai Chen, Wenfei Li, Zhi Qi

{"title":"Deciphering the molecular mechanism underlying morphology transition in two-component DNA-protein cophase separation","authors":"Cheng Li, Yunqiang Bian, Yiting Tang, Lingyu Meng, Peipei Yin, Ye Hong, Jun Cheng, Yuchen Li, Jie Lin, Chao Tang, Chunlai Chen, Wenfei Li, Zhi Qi","doi":"10.1016/j.str.2024.10.026","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.026","url":null,"abstract":"Nucleic acid and protein co-condensates exhibit diverse morphologies crucial for fundamental cellular processes. Despite many previous studies that advanced our understanding of this topic, several interesting biophysical questions regarding the underlying molecular mechanisms remain. We investigated DNA and human transcription factor p53 co-condensates—a scenario where neither dsDNA nor the protein demonstrates phase-separation behavior individually. Through a combination of experimental assays and theoretical approaches, we elucidated: (1) the phase diagram of DNA-protein co-condensates at a certain observation time, identifying a phase transition between viscoelastic fluid and viscoelastic solid states, and a morphology transition from droplet-like to “pearl chain”-like co-condensates; (2) the growth dynamics of co-condensates. Droplet-like and “pearl chain”-like co-condensates share a common initial critical microscopic cluster size at the nanometer scale during the early stage of phase separation. These findings provide important insights into the biophysical mechanisms underlying multi-component phase separation within cellular environments.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"216 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanism of negative μ-opioid receptor modulation by sodium ions 钠离子调节负μ-阿片受体的机制

IF 5.7 2区生物学

Structure Pub Date : 2024-11-12 DOI: 10.1016/j.str.2024.10.023

Neil J. Thomson, Ulrich Zachariae

引用次数: 0

Targeting adhesion G protein-coupled receptors. Current status and future perspectives 靶向粘附 G 蛋白偶联受体。现状与未来展望

IF 5.7 2区生物学

Structure Pub Date : 2024-11-08 DOI: 10.1016/j.str.2024.10.022

Fabian Liessmann, Lukas von Bredow, Jens Meiler, Ines Liebscher

{"title":"Targeting adhesion G protein-coupled receptors. Current status and future perspectives","authors":"Fabian Liessmann, Lukas von Bredow, Jens Meiler, Ines Liebscher","doi":"10.1016/j.str.2024.10.022","DOIUrl":"https://doi.org/10.1016/j.str.2024.10.022","url":null,"abstract":"G protein-coupled receptors (GPCRs) orchestrate many physiological functions and are a crucial target in drug discovery. Adhesion GPCRs (aGPCRs), the second largest family within this superfamily, are promising yet underexplored targets for treating various diseases, including obesity, psychiatric disorders, and cancer. However, the receptors’ unique and complex structure and miscellaneous interactions complicate comprehensive pharmacological studies. Despite recent progress in determining structures and elucidation of the activation mechanism, the function of many receptors remains to be determined.This review consolidates current knowledge on aGPCR ligands, focusing on small molecule orthosteric ligands and allosteric modulators identified for the ADGRGs subfamily (subfamily VIII), (GPR56/ADGRG1, GPR64/ADGRG2, GPR97/ADGRG3, GPR114/ADGRG5, GPR126/ADGRG6, and GPR128/ADGRG7). We discuss challenges in hit identification, target validation, and drug discovery, highlighting molecular compositions and recent structural breakthroughs. ADGRG ligands can offer new insights into aGPCR modulation and have significant potential for novel therapeutic interventions targeting various diseases.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"145 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ringing the changes: Regulation of Parkin activity by different ubiquitin and ubiquitin-like proteins 环形变化：不同泛素和泛素样蛋白对 Parkin 活性的调控

IF 5.7 2区生物学

Structure Pub Date : 2024-11-07 DOI: 10.1016/j.str.2024.10.015

Shalini Iyer, Chittaranjan Das

引用次数: 0

Multi-step shapeshifting of SARS-CoV-2 Omicron spikes during fusion SARS-CoV-2 Omicron 穗状病毒在融合过程中的多步变形

IF 5.7 2区生物学

Structure Pub Date : 2024-11-07 DOI: 10.1016/j.str.2024.10.017

Wang Xu, Yang Han, Maolin Lu

引用次数: 0

Traces of convergent evolution left in the structure of EgtB-IV EgtB-IV 结构中留下的趋同进化痕迹