Structure最新文献_第3页

Capsid structure of phage SPO1 reveals novel minor capsid proteins and insights into capsid stabilization 噬菌体SPO1的衣壳结构揭示了新的次要衣壳蛋白和衣壳稳定的见解

IF 5.7 2区生物学

Structure Pub Date : 2025-08-29 DOI: 10.1016/j.str.2025.08.004

Xinyue Zhao, Aohan Wang, Yueting Wang, Yue Kang, Qianqian Shao, Lin Li, Yaqi Zheng, Hongli Hu, Xiangyun Li, Hongling Fan, Can Cai, Bing Liu, Qianglin Fang

引用次数: 0

Mettl15-Mettl17 modulates the transition from early to late pre-mitoribosome Mettl15-Mettl17调节从早期到晚期前线粒体的转变

IF 5.7 2区生物学

Structure Pub Date : 2025-08-28 DOI: 10.1016/j.str.2025.08.002

Yury Zgadzay, Claudio Mirabello, George Wanes, Tomáš Pánek, Prashant Chauhan, Björn Nystedt, Alena Zíková, Paul C. Whitford, Ondřej Gahura, Alexey Amunts

引用次数: 0

Light-induced conformational switching and magnetic sensitivity of Drosophila cryptochrome 果蝇隐花色素的光诱导构象开关和磁敏感性

IF 5.7 2区生物学

Structure Pub Date : 2025-08-28 DOI: 10.1016/j.str.2025.08.003

Shane A. Chandler, Angela S. Gehrckens, Laila M.N. Shah, Katherine E. Buckton, Guodong Cao, Navoneel Sen, Tilo Zollitsch, Ryan Rodriguez, Ilia A. Solov’yov, Erik Schleicher, Stefan Weber, P.J. Hore, Christiane R. Timmel, Stuart R. Mackenzie, Justin L.P. Benesch

{"title":"Light-induced conformational switching and magnetic sensitivity of Drosophila cryptochrome","authors":"Shane A. Chandler, Angela S. Gehrckens, Laila M.N. Shah, Katherine E. Buckton, Guodong Cao, Navoneel Sen, Tilo Zollitsch, Ryan Rodriguez, Ilia A. Solov’yov, Erik Schleicher, Stefan Weber, P.J. Hore, Christiane R. Timmel, Stuart R. Mackenzie, Justin L.P. Benesch","doi":"10.1016/j.str.2025.08.003","DOIUrl":"https://doi.org/10.1016/j.str.2025.08.003","url":null,"abstract":"Cryptochromes are light-sensitive flavoproteins with various biological roles, including a proposed function in magnetoreception. This mechanism rests on a magnetically sensitive photochemical reaction of the flavin chromophore with a chain of tryptophan residues within the protein scaffold. However, the protein-mediated mechanisms of magnetic signal transduction are unclear. We have examined the response of an archetypal cryptochrome, DmCRY, to photochemical activation by means of hydrogen-deuterium exchange mass spectrometry, complemented by molecular dynamics simulations and cavity ring-down spectroscopy. We were able to measure the dynamics of DmCRY at near-residue level resolution, revealing a reversible, long-lived, blue-light induced conformational change in the protein’s C-terminal tail. This putative signaling state was validated using different illumination conditions, and by examining DmCRY variants in which the electron transfer chain was perturbed. Our results show how the photochemical behavior of the flavin chromophore generates a state of DmCRY that may initiate downstream interactions.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"23 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144911222","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

Design of a selective peptide inhibitor targeting KDM5C demethylase activity 靶向KDM5C去甲基酶活性的选择性肽抑制剂的设计

IF 5.7 2区生物学

Structure Pub Date : 2025-08-27 DOI: 10.1016/j.str.2025.08.001

Valentina Lukinović, Hemanta Adhikary, Matthew Hoekstra, Ali Shukri, Francois Charih, Anand Chopra, Kyle K. Biggar

{"title":"Design of a selective peptide inhibitor targeting KDM5C demethylase activity","authors":"Valentina Lukinović, Hemanta Adhikary, Matthew Hoekstra, Ali Shukri, Francois Charih, Anand Chopra, Kyle K. Biggar","doi":"10.1016/j.str.2025.08.001","DOIUrl":"https://doi.org/10.1016/j.str.2025.08.001","url":null,"abstract":"Post-translational modifications, particularly protein lysine demethylation, intricately regulate diverse cellular processes. Dysregulation of this modification often precipitates human pathologies by perturbing substrate protein functions, stability, and interactions. Lysine demethylases (KDMs), such as the KDM5 family, are crucial in removing methyl marks. In particular, KDM5C has gained prominence for its role in cancer biology and drug resistance. These enzymes, specializing in erasing lysine methylation marks—especially from histone H3 lysine 4 (H3K4)—directly influence gene transcription. This study pioneers the design of a peptide inhibitor of KDM5C demethylase activity. This novel inhibitor displays remarkable selectivity for KDM5C over other family members. Intriguingly, in vivo experiments demonstrate that this inhibitor significantly reduces tumor growth. These findings highlight the potential of targeting KDM5C inhibition as a strategy for colon cancer treatment. Moreover, these findings underscore the promise of peptide inhibitors as targeted therapies, emphasizing their potential in altering the trajectory of cancer therapeutics.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"16 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906077","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

Secretory stimuli distinctly regulate insulin secretory granule maturation through structural remodeling 分泌刺激通过结构重塑明显调节胰岛素分泌颗粒成熟

IF 5.7 2区生物学

Structure Pub Date : 2025-08-26 DOI: 10.1016/j.str.2025.07.022

Aneesh Deshmukh, Kevin Chang, Janielle Cuala, Maria J. Hernandez Campos, Shayan Mahmood, Riva Verma, Senta Georgia, Valentina Loconte, Kate L. White

{"title":"Secretory stimuli distinctly regulate insulin secretory granule maturation through structural remodeling","authors":"Aneesh Deshmukh, Kevin Chang, Janielle Cuala, Maria J. Hernandez Campos, Shayan Mahmood, Riva Verma, Senta Georgia, Valentina Loconte, Kate L. White","doi":"10.1016/j.str.2025.07.022","DOIUrl":"https://doi.org/10.1016/j.str.2025.07.022","url":null,"abstract":"Insulin secretory granule (ISG) maturation is a crucial aspect of insulin secretion and glucose homeostasis. The regulation of this maturation remains poorly understood, especially how secretory stimuli affect ISG maturity and subcellular localization. In this study, we used soft X-ray tomography (SXT) to quantitatively map ISG morphology, density, and location in single INS-1E and mouse pancreatic β cells under the effect of various secretory stimuli. We found that the activation of glucokinase (GK), gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide-1 receptor (GLP-1R), and G protein-coupled receptor 40 (GPR40) promotes ISG maturation. Each stimulus induces unique structural remodeling in ISGs, by altering size and density, depending on the specific signaling cascades activated. These distinct ISG subpopulations mobilize and redistribute in the cell, altering the overall cellular structural organization. Our results provide insight into how current diabetes and obesity therapies impact ISG maturation and may inform the development of future treatments that target maturation specifically.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"53 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900398","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

Chloride binding does not influence prestin motor speed at very high frequencies in the mouse outer hair cell 在小鼠外毛细胞中，氯离子结合在非常高的频率下不影响prestin运动速度

IF 5.7 2区生物学

Structure Pub Date : 2025-08-26 DOI: 10.1016/j.str.2025.08.016

Jun-Ping Bai, Chenou Zhang, Iman Bahader, Nicola Strenzke, Vijay Renigunta, Dominik Oliver, Dhasakumar Navaratnam, Oliver Beckstein, Joseph Santos-Sacchi

引用次数: 0

Cryo-EM structure of a cell-free synthesized full-length human β1-adrenergic receptor in complex with Gs 无细胞合成的人β1-肾上腺素能受体与Gs复合物的低温电镜结构

IF 5.7 2区生物学

Structure Pub Date : 2025-08-25 DOI: 10.1016/j.str.2025.07.020

Felipe Merino, Zoe Köck, Utz Ermel, Philipp Dahlhaus, Anna Grimm, Anja Seybert, Jan Kubicek, Achilleas S. Frangakis, Volker Dötsch, Daniel Hilger, Frank Bernhard

{"title":"Cryo-EM structure of a cell-free synthesized full-length human β1-adrenergic receptor in complex with Gs","authors":"Felipe Merino, Zoe Köck, Utz Ermel, Philipp Dahlhaus, Anna Grimm, Anja Seybert, Jan Kubicek, Achilleas S. Frangakis, Volker Dötsch, Daniel Hilger, Frank Bernhard","doi":"10.1016/j.str.2025.07.020","DOIUrl":"https://doi.org/10.1016/j.str.2025.07.020","url":null,"abstract":"The third intracellular loop (ICL3) of the β1-adrenergic receptor (β1AR) plays a critical role in regulating G protein coupling, yet the structural basis has remained unclear due to truncations of ICL3 in all available structures of the β1AR in complex with Gs or a G protein mimetic nanobody. To address this, we used cell-free cotranslational insertion of full-length human β1AR into nanodiscs and determined its cryo-electron microscopy (cryo-EM) structure in complex with Gs. In this structure, ICL3 extends transmembrane helix 5, resulting in enhanced interactions with Gαs and in a slight rotation of the engaged G protein. This repositioning enables new polar interactions between Gαs, ICL2 and helix 8, while ICL1 and helix 8 form additional contacts with Gβ. These structural insights, supported by mutational analysis, demonstrate that ICL3 enhances G protein activation and downstream cAMP signaling by promoting more extensive interactions between the receptor and the heterotrimeric G protein.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"21 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900401","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

Design of multi-target peptide modulators for protein chaperone networks 蛋白伴侣网络多靶点肽调节剂的设计

IF 5.7 2区生物学

Structure Pub Date : 2025-08-25 DOI: 10.1016/j.str.2025.07.021

Luca Torielli, Matteo Castelli, Francesca Milani, Jennifer A. Heritz, Sara J. Cayaban, Jason Hernandez, Stefano A. Serapian, Andrea Magni, Elena Frasnetti, Filippo Doria, Valentina Pirota, Laura A. Wengert, Mark R. Woodford, Giulia Lodigiani, Greta Bergamaschi, Marina Veronesi, Tiziano Bandiera, Stefania Girotto, Antonella Paladino, Chrisostomos Prodromou, Giorgio Colombo

{"title":"Design of multi-target peptide modulators for protein chaperone networks","authors":"Luca Torielli, Matteo Castelli, Francesca Milani, Jennifer A. Heritz, Sara J. Cayaban, Jason Hernandez, Stefano A. Serapian, Andrea Magni, Elena Frasnetti, Filippo Doria, Valentina Pirota, Laura A. Wengert, Mark R. Woodford, Giulia Lodigiani, Greta Bergamaschi, Marina Veronesi, Tiziano Bandiera, Stefania Girotto, Antonella Paladino, Chrisostomos Prodromou, Giorgio Colombo","doi":"10.1016/j.str.2025.07.021","DOIUrl":"https://doi.org/10.1016/j.str.2025.07.021","url":null,"abstract":"Essential chaperones heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90) collaborate in oncoprotein folding. Dual inhibition of these chaperones has shown synergy in preclinical studies but remains challenging to achieve. Using a computational approach, we designed peptides mimicking the predicted unfolding regions of Kinase CDK4, a client protein of both Hsp70 and Hsp90. Peptide Cdk4-2 is shown to simultaneously bind Hsp70, Hsp90, and co-chaperone Cdc37. Cdk4-2 is membrane permeable, inhibits CDK4-mediated retinoblastoma phosphorylation, and induces apoptosis in renal carcinoma cells. Structure-function studies identified a minimal pharmacophore for Hsp70 binding and critical interactions for peptide affinity. These findings demonstrate the feasibility of rationally designing multi-target modulators of chaperone networks. Cdk4-2 is a promising lead for therapeutic development, expanding the molecular space of modulators of cancer-associated multiprotein machineries. While focused on chaperones, the idea behind our strategy is general and immediately transferable to other multiprotein targets and networks.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"1 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144900400","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

Cryo-EM structures of human OAT1 reveal drug binding and inhibition mechanisms 人OAT1的低温电镜结构揭示了药物结合和抑制机制

IF 5.7 2区生物学

Structure Pub Date : 2025-08-21 DOI: 10.1016/j.str.2025.07.019

Hyung-Min Jeon, Jisung Eun, Kelly H. Kim, Youngjin Kim

引用次数: 0

Nanobodies restore stability to cancer-associated mutants of tumor suppressor protein p16INK4a 纳米体恢复肿瘤抑制蛋白p16INK4a癌症相关突变体的稳定性

IF 5.7 2区生物学

Structure Pub Date : 2025-08-14 DOI: 10.1016/j.str.2025.07.017

Owen Burbidge, Martyna W. Pastok, Diana Papini, Samantha L. Hodder, Grasilda Zenkevičiūtė, Kenneth Z.J. Tan, Shannon Turberville, Martin E.M. Noble, Jane A. Endicott, Laura Itzhaki

{"title":"Nanobodies restore stability to cancer-associated mutants of tumor suppressor protein p16INK4a","authors":"Owen Burbidge, Martyna W. Pastok, Diana Papini, Samantha L. Hodder, Grasilda Zenkevičiūtė, Kenneth Z.J. Tan, Shannon Turberville, Martin E.M. Noble, Jane A. Endicott, Laura Itzhaki","doi":"10.1016/j.str.2025.07.017","DOIUrl":"https://doi.org/10.1016/j.str.2025.07.017","url":null,"abstract":"We describe the generation and characterization of camelid single-domain antibodies (nanobodies) raised against tumor suppressor protein p16INK4a (p16). p16 is a cell cycle regulator that inhibits cyclin-dependent kinases CDK4 and CDK6 and is inactivated in sporadic and familial cancers. The majority of p16 missense mutations cause loss of function by destabilizing the protein’s structure. We identify nanobodies that bind p16 with nanomolar affinities and restore the stability of many different cancer-associated p16 mutations located at sites throughout the protein. The crystal structure of a nanobody-p16 complex reveals that the nanobody binds to the opposite face of p16 to the CDK-binding interface permitting formation of a ternary complex. We confirm that nanobodies bind to p16 in a cellular setting and do not preclude p16 binding to CDK6 and its ability to induce cell-cycle arrest. These findings indicate that nanobodies merit testing as pharmacological chaperones for p16 reactivation in the cell.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"40 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840308","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