Pub Date : 2025-09-03DOI: 10.1016/j.str.2025.08.011
Daria Trofimova, Caitlin Doubleday, Byron Hunter, Jesus Danilo Serrano Arevalo, Emma Davison, Eric Wen, Kim Munro, John S. Allingham
Kinesin-8 motors regulate kinetochore-microtubule dynamics and control spindle length and positioning. Certain isoforms achieve this by traversing microtubules, accumulating at plus-ends, and depolymerizing terminal αβ-tubulin subunits. While the kinesin-8 motor domain is well characterized, the tail domain regions are less understood. Using the Candida albicans Kip3 protein as a model for fungal kinesin-8, we present an X-ray crystal structure and hydrodynamic analysis of its motor-proximal tail segment, revealing its role in motor dimerization. This segment forms a compact, 92 Å-long four-helix bundle, rather than an elongated coiled-coil stalk seen in most kinesins. The bundle is stabilized primarily by interactions between helices one and three, with additional support from helices two and four. A flexible hinge bisects the bundle into two lobules, imparting mechanical pliability and asymmetric exterior surfaces. These unique features may facilitate interactions with regulatory elements or contribute to the functional versatility of kinesin-8 motors.
{"title":"Fungal kinesin-8 motors dimerize by folding their proximal tail domain into a compact helical bundle","authors":"Daria Trofimova, Caitlin Doubleday, Byron Hunter, Jesus Danilo Serrano Arevalo, Emma Davison, Eric Wen, Kim Munro, John S. Allingham","doi":"10.1016/j.str.2025.08.011","DOIUrl":"https://doi.org/10.1016/j.str.2025.08.011","url":null,"abstract":"Kinesin-8 motors regulate kinetochore-microtubule dynamics and control spindle length and positioning. Certain isoforms achieve this by traversing microtubules, accumulating at plus-ends, and depolymerizing terminal αβ-tubulin subunits. While the kinesin-8 motor domain is well characterized, the tail domain regions are less understood. Using the <em>Candida albicans</em> Kip3 protein as a model for fungal kinesin-8, we present an X-ray crystal structure and hydrodynamic analysis of its motor-proximal tail segment, revealing its role in motor dimerization. This segment forms a compact, 92 Å-long four-helix bundle, rather than an elongated coiled-coil stalk seen in most kinesins. The bundle is stabilized primarily by interactions between helices one and three, with additional support from helices two and four. A flexible hinge bisects the bundle into two lobules, imparting mechanical pliability and asymmetric exterior surfaces. These unique features may facilitate interactions with regulatory elements or contribute to the functional versatility of kinesin-8 motors.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"11 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930865","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}
Pub Date : 2025-09-02DOI: 10.1016/j.str.2025.08.009
Evan Billings, Zixing Fan, Moloud Aflaki Sooreshjani, James C. Gumbart, Nicholas Noinaj
N. gonorrhoeae (Ngo) causes the sexually transmitted infection gonorrhea with ∼106 million infections worldwide annually. Ngo infections can result in an increased risk of acquiring HIV, infertility, and blindness. To combat Ngo infections, we report the cryoelectron microscopy (cryo-EM) structure of the Ngo β-barrel assembly machinery (NgBAM), which is responsible for the biogenesis of β-barrel outer membrane proteins (OMPs). NgBAM was observed in an inward-open state; however, the polypeptide transport-associated (POTRA) domains more closely match those found in the outward-open state in E. coli β-barrel assembly machinery (BAM). The barrel seam of NgBamA consists of partial pairing of strand β1 with β16; no outward-open state of NgBAM was observed. Molecular dynamics (MD) simulations reveal unique overall dynamics and interplay between the POTRA domains of NgBamA and NgBamD. We propose that in Ngo, initial recognition occurs in the inward-open state where the last strand of the OMP partially pairs with β1 of NgBamA and must compete off β16.
{"title":"Structural insights into outer membrane protein biogenesis in pathogenic Neisseria","authors":"Evan Billings, Zixing Fan, Moloud Aflaki Sooreshjani, James C. Gumbart, Nicholas Noinaj","doi":"10.1016/j.str.2025.08.009","DOIUrl":"https://doi.org/10.1016/j.str.2025.08.009","url":null,"abstract":"<em>N.</em> g<em>onorrhoeae</em> (Ngo) causes the sexually transmitted infection gonorrhea with ∼106 million infections worldwide annually. Ngo infections can result in an increased risk of acquiring HIV, infertility, and blindness. To combat Ngo infections, we report the cryoelectron microscopy (cryo-EM) structure of the Ngo β-barrel assembly machinery (<em>Ng</em>BAM), which is responsible for the biogenesis of β-barrel outer membrane proteins (OMPs). <em>Ng</em>BAM was observed in an inward-open state; however, the polypeptide transport-associated (POTRA) domains more closely match those found in the outward-open state in <em>E</em>. <em>coli</em> β-barrel assembly machinery (BAM). The barrel seam of <em>Ng</em>BamA consists of partial pairing of strand β1 with β16; no outward-open state of <em>Ng</em>BAM was observed. Molecular dynamics (MD) simulations reveal unique overall dynamics and interplay between the POTRA domains of <em>Ng</em>BamA and <em>Ng</em>BamD. We propose that in Ngo, initial recognition occurs in the inward-open state where the last strand of the OMP partially pairs with β1 of <em>Ng</em>BamA and must compete off β16.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"14 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928517","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}
Pub Date : 2025-09-01DOI: 10.1016/j.str.2025.08.008
Claire Overly Cottom, Eva Heinz, Satchal Erramilli, Anthony Kossiakoff, Daniel J. Slade, Nicholas Noinaj
F. nucleatum is a Gram-negative bacteria that causes oral infections and is linked to colorectal cancer. Pathogenicity relies on a type of β-barrel outer membrane protein (OMP) called an autotransporter. The biogenesis of OMPs is typically mediated by the barrel assembly machinery (BAM) complex. In this study, we investigate the evolution, composition, and structure of the OMP biogenesis machinery in F. nucleatum. Our bioinformatics and proteomics analyses indicate that OMP biogenesis in F. nucleatum is mediated solely by the core component BamA. The structure of FnBamA highlights distinct features, including four POTRA domains and a C-terminal 16-stranded β-barrel domain observed as an inverted dimer. FnBamA represents the original composition of the assembly machinery, and a duplication event that resulted in BamA and TamA occurred after the split of other lineages, including the Proteobacteria, from the Fusobacteria. FnBamA, therefore, likely serves a singular role in the biogenesis of all OMPs.
{"title":"Characterization of the OMP biogenesis machinery in Fusobacterium nucleatum","authors":"Claire Overly Cottom, Eva Heinz, Satchal Erramilli, Anthony Kossiakoff, Daniel J. Slade, Nicholas Noinaj","doi":"10.1016/j.str.2025.08.008","DOIUrl":"https://doi.org/10.1016/j.str.2025.08.008","url":null,"abstract":"F. <em>nucleatum</em> is a Gram-negative bacteria that causes oral infections and is linked to colorectal cancer. Pathogenicity relies on a type of β-barrel outer membrane protein (OMP) called an autotransporter. The biogenesis of OMPs is typically mediated by the barrel assembly machinery (BAM) complex. In this study, we investigate the evolution, composition, and structure of the OMP biogenesis machinery in <em>F. nucleatum</em>. Our bioinformatics and proteomics analyses indicate that OMP biogenesis in <em>F. nucleatum</em> is mediated solely by the core component BamA. The structure of <em>Fn</em>BamA highlights distinct features, including four POTRA domains and a C-terminal 16-stranded β-barrel domain observed as an inverted dimer. <em>Fn</em>BamA represents the original composition of the assembly machinery, and a duplication event that resulted in BamA and TamA occurred after the split of other lineages, including the <em>Proteobacteria</em>, from the <em>Fusobacteria</em>. <em>Fn</em>BamA, therefore, likely serves a singular role in the biogenesis of all OMPs.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"25 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144924259","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}
Pub Date : 2025-09-01DOI: 10.1016/j.str.2025.08.007
Daniel R. Fox, Cyntia Taveneau, Janik Clement, Rhys Grinter, Gavin J. Knott
The application of artificial intelligence to structural biology has transformed protein design from a conceptual challenge into a practical approach for creating new-to-nature proteins. By leveraging machine learning, researchers can now computationally design proteins with tailored architectures and binding specificities. This has enabled the rapid in silico generation of high-affinity binders to diverse and previously intractable targets. This approach dramatically reduces binder development time and resource requirements, compared to traditional experimental approaches, while improving hit rates and designability. Recent successes include the creation of binding proteins that neutralize toxins, modulate immune pathways, and engage disordered targets with high affinity and specificity. Improvements in model accuracy are expanding the scope of what can be designed, while characterization in preclinical models is paving the way for therapeutic development. De novo binder design represents a paradigm shift in protein engineering, where custom binders can now be programmed to meet specific biological challenges.
{"title":"Code to complex: AI-driven de novo binder design","authors":"Daniel R. Fox, Cyntia Taveneau, Janik Clement, Rhys Grinter, Gavin J. Knott","doi":"10.1016/j.str.2025.08.007","DOIUrl":"https://doi.org/10.1016/j.str.2025.08.007","url":null,"abstract":"The application of artificial intelligence to structural biology has transformed protein design from a conceptual challenge into a practical approach for creating new-to-nature proteins. By leveraging machine learning, researchers can now computationally design proteins with tailored architectures and binding specificities. This has enabled the rapid <em>in silico</em> generation of high-affinity binders to diverse and previously intractable targets. This approach dramatically reduces binder development time and resource requirements, compared to traditional experimental approaches, while improving hit rates and designability. Recent successes include the creation of binding proteins that neutralize toxins, modulate immune pathways, and engage disordered targets with high affinity and specificity. Improvements in model accuracy are expanding the scope of what can be designed, while characterization in preclinical models is paving the way for therapeutic development. <em>De novo</em> binder design represents a paradigm shift in protein engineering, where custom binders can now be programmed to meet specific biological challenges.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"31 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144924257","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}
SPO1-related bacteriophages are promising candidates for phage therapy. We present the 3.0 Å cryo-electron microscopy (cryo-EM) structure of the SPO1 capsid with a triangulation number T = 16, enabling the construction of an atomic model comprising the major capsid protein and three types of minor capsid proteins: gp29.2, gp2.7, and gp36.3. These minor capsid proteins adopt novel folds. They might stabilize the capsid and determine its curvature. Gp29.2 monomers contain a three-blade propeller fold and are located at the 3-fold and quasi-three-fold axes. Gp2.7 forms pentamers atop pentameric capsomers, while gp36.3 binds to the capsid’s inner surface, forming star-shaped structures increasing connections between pentameric and hexameric capsomers. The surface exposed regions of gp29.2 and gp2.7 make SPO1 of interest as a nanocage for phage display. Our findings advance the understanding of capsid architecture, stabilization, and local curvature determination for SPO1-related bacteriophages.
{"title":"Capsid structure of phage SPO1 reveals novel minor capsid proteins and insights into capsid stabilization","authors":"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","doi":"10.1016/j.str.2025.08.004","DOIUrl":"https://doi.org/10.1016/j.str.2025.08.004","url":null,"abstract":"SPO1-related bacteriophages are promising candidates for phage therapy. We present the 3.0 Å cryo-electron microscopy (cryo-EM) structure of the SPO1 capsid with a triangulation number T = 16, enabling the construction of an atomic model comprising the major capsid protein and three types of minor capsid proteins: gp29.2, gp2.7, and gp36.3. These minor capsid proteins adopt novel folds. They might stabilize the capsid and determine its curvature. Gp29.2 monomers contain a three-blade propeller fold and are located at the 3-fold and quasi-three-fold axes. Gp2.7 forms pentamers atop pentameric capsomers, while gp36.3 binds to the capsid’s inner surface, forming star-shaped structures increasing connections between pentameric and hexameric capsomers. The surface exposed regions of gp29.2 and gp2.7 make SPO1 of interest as a nanocage for phage display. Our findings advance the understanding of capsid architecture, stabilization, and local curvature determination for SPO1-related bacteriophages.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"8 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915925","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}
Pub Date : 2025-08-28DOI: 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
The biogenesis of the mitoribosomal small subunit involves a dynamic network of assembly factors. Conserved methyltransferases Mettl15 and Mettl17 act on the solvent-exposed surface of rRNA. Binding of Mettl17 is associated with the early assembly stage, whereas Mettl15 is involved in the late stage. Here, we integrate structural data from Trypanosoma brucei with mammalian homologs and molecular dynamics simulations. We reveal how the interplay of Mettl15 and Mettl17 in intermediate steps links the distinct stages of small subunit assembly. The analysis suggests a model wherein Mettl17 acts as a platform for Mettl15 recruitment. Subsequent release of Mettl17 allows a conformational change of Mettl15 for substrate recognition. Upon methylation, Mettl15 adopts a loosely bound state which leads to its replacement by initiation factors, concluding the assembly. Together, our results indicate that assembly factors Mettl15 and Mettl17 cooperate to regulate the biogenesis process.
{"title":"Mettl15-Mettl17 modulates the transition from early to late pre-mitoribosome","authors":"Yury Zgadzay, Claudio Mirabello, George Wanes, Tomáš Pánek, Prashant Chauhan, Björn Nystedt, Alena Zíková, Paul C. Whitford, Ondřej Gahura, Alexey Amunts","doi":"10.1016/j.str.2025.08.002","DOIUrl":"https://doi.org/10.1016/j.str.2025.08.002","url":null,"abstract":"The biogenesis of the mitoribosomal small subunit involves a dynamic network of assembly factors. Conserved methyltransferases Mettl15 and Mettl17 act on the solvent-exposed surface of rRNA. Binding of Mettl17 is associated with the early assembly stage, whereas Mettl15 is involved in the late stage. Here, we integrate structural data from <em>Trypanosoma brucei</em> with mammalian homologs and molecular dynamics simulations. We reveal how the interplay of Mettl15 and Mettl17 in intermediate steps links the distinct stages of small subunit assembly. The analysis suggests a model wherein Mettl17 acts as a platform for Mettl15 recruitment. Subsequent release of Mettl17 allows a conformational change of Mettl15 for substrate recognition. Upon methylation, Mettl15 adopts a loosely bound state which leads to its replacement by initiation factors, concluding the assembly. Together, our results indicate that assembly factors Mettl15 and Mettl17 cooperate to regulate the biogenesis process.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"430 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144911233","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}
Pub Date : 2025-08-28DOI: 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
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.
{"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, <em>Dm</em>CRY, 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 <em>Dm</em>CRY 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 <em>Dm</em>CRY variants in which the electron transfer chain was perturbed. Our results show how the photochemical behavior of the flavin chromophore generates a state of <em>Dm</em>CRY 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}
Pub Date : 2025-08-27DOI: 10.1016/j.str.2025.08.001
Valentina Lukinović, Hemanta Adhikary, Matthew Hoekstra, Ali Shukri, Francois Charih, Anand Chopra, Kyle K. Biggar
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.
{"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, <em>in vivo</em> 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}
Pub Date : 2025-08-26DOI: 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
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.
{"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}
Pub Date : 2025-08-26DOI: 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
(Structure 33, 1417–1424.e1-e3; August 7, 2025)
（结构33,1417-1424.e1-e3； 2025年8月7日）
{"title":"Chloride binding does not influence prestin motor speed at very high frequencies in the mouse outer hair cell","authors":"Jun-Ping Bai, Chenou Zhang, Iman Bahader, Nicola Strenzke, Vijay Renigunta, Dominik Oliver, Dhasakumar Navaratnam, Oliver Beckstein, Joseph Santos-Sacchi","doi":"10.1016/j.str.2025.08.016","DOIUrl":"https://doi.org/10.1016/j.str.2025.08.016","url":null,"abstract":"(Structure <em>33</em>, 1417–1424.e1-e3; August 7, 2025)","PeriodicalId":22168,"journal":{"name":"Structure","volume":"28 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906078","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}
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