Pub Date : 2025-12-01DOI: 10.1038/s41594-025-01703-5
Vita Vidmar, Céline Borde, Lisa Bruno, Nataliya Miropolskaya, Maria Takacs, Claire Batisse, Charlotte Saint-André, Chengjin Zhu, Olivier Espéli, Valérie Lamour, Albert Weixlbaumer
During transcription, RNA polymerase (RNAP) continuously unwinds and rewinds DNA, generating negative and positive supercoils upstream and downstream, respectively. Using single-particle cryo-EM, we elucidated how bacterial RNAP and DNA topoisomerase I (TopoI), which relaxes negative supercoils, operate in close spatial proximity. TopoI binds to relaxed DNA upstream of RNAP, and this involves a conformational switch in the TopoI functional domains. This suggests that TopoI exerts a sensing role before the formation of negative supercoils. On DNA substrates mimicking negatively supercoiled DNA, TopoI threads one strand into the active site for cleavage and binds the complementary strand with an auxiliary domain. Transcriptomic and phenotypic analyses suggest that mutations affecting conformational changes in TopoI impact gene expression and operon polarity in bacteria. In summary, we propose a comprehensive model for DNA relaxation in the proximity of active bacterial transcription. Vidmar et al. use cryo-EM to reveal how bacterial RNA polymerase (RNAP) and topoisomerase I (TopoI) cooperate. TopoI switches conformation, senses DNA supercoils near RNAP and relaxes them. Mutations disrupting this process alter bacterial motility and operon polarity.
{"title":"DNA topoisomerase I acts as supercoiling sensor for bacterial transcription elongation","authors":"Vita Vidmar, Céline Borde, Lisa Bruno, Nataliya Miropolskaya, Maria Takacs, Claire Batisse, Charlotte Saint-André, Chengjin Zhu, Olivier Espéli, Valérie Lamour, Albert Weixlbaumer","doi":"10.1038/s41594-025-01703-5","DOIUrl":"10.1038/s41594-025-01703-5","url":null,"abstract":"During transcription, RNA polymerase (RNAP) continuously unwinds and rewinds DNA, generating negative and positive supercoils upstream and downstream, respectively. Using single-particle cryo-EM, we elucidated how bacterial RNAP and DNA topoisomerase I (TopoI), which relaxes negative supercoils, operate in close spatial proximity. TopoI binds to relaxed DNA upstream of RNAP, and this involves a conformational switch in the TopoI functional domains. This suggests that TopoI exerts a sensing role before the formation of negative supercoils. On DNA substrates mimicking negatively supercoiled DNA, TopoI threads one strand into the active site for cleavage and binds the complementary strand with an auxiliary domain. Transcriptomic and phenotypic analyses suggest that mutations affecting conformational changes in TopoI impact gene expression and operon polarity in bacteria. In summary, we propose a comprehensive model for DNA relaxation in the proximity of active bacterial transcription. Vidmar et al. use cryo-EM to reveal how bacterial RNA polymerase (RNAP) and topoisomerase I (TopoI) cooperate. TopoI switches conformation, senses DNA supercoils near RNAP and relaxes them. Mutations disrupting this process alter bacterial motility and operon polarity.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"134-144"},"PeriodicalIF":10.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145645166","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}
Pub Date : 2025-11-27DOI: 10.1038/s41594-025-01720-4
Cells store excess fat in lipid droplets to avoid lipotoxicity and maintain homeostasis. We identified an autophagy-independent role for the autophagy lipid transfer protein ATG2A in helping direct lipids to growing lipid droplets and promoting recruitment of the enzyme DGAT2. This coordination enhances triglyceride storage, protects the endoplasmic reticulum from lipid overload and limits the misrouting of lipids into other metabolic pathways.
{"title":"ATG2A–DGAT2 cooperation fuels lipid droplet growth","authors":"","doi":"10.1038/s41594-025-01720-4","DOIUrl":"10.1038/s41594-025-01720-4","url":null,"abstract":"Cells store excess fat in lipid droplets to avoid lipotoxicity and maintain homeostasis. We identified an autophagy-independent role for the autophagy lipid transfer protein ATG2A in helping direct lipids to growing lipid droplets and promoting recruitment of the enzyme DGAT2. This coordination enhances triglyceride storage, protects the endoplasmic reticulum from lipid overload and limits the misrouting of lipids into other metabolic pathways.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2385-2386"},"PeriodicalIF":10.1,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609471","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}
Pub Date : 2025-11-20DOI: 10.1038/s41594-025-01722-2
Heesoo Uhm, Sangsu Bae
Artificial intelligence (AI) is advancing genome editing, from predictive modeling to generative design. Emerging generative AI tools such as RFdiffusion, AlphaFold 3 and ESM now facilitate the de novo design of linkers, inhibitors and enzymes. We highlight work where AI-driven design is used to enhance the precision of mitochondrial cytosine base editors.
{"title":"Expansion of artificial intelligence for genome editing","authors":"Heesoo Uhm, Sangsu Bae","doi":"10.1038/s41594-025-01722-2","DOIUrl":"10.1038/s41594-025-01722-2","url":null,"abstract":"Artificial intelligence (AI) is advancing genome editing, from predictive modeling to generative design. Emerging generative AI tools such as RFdiffusion, AlphaFold 3 and ESM now facilitate the de novo design of linkers, inhibitors and enzymes. We highlight work where AI-driven design is used to enhance the precision of mitochondrial cytosine base editors.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2380-2382"},"PeriodicalIF":10.1,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554401","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}
Pub Date : 2025-11-17DOI: 10.1038/s41594-025-01715-1
Domagoj Baretić, Sophia Missoury, Karishma Patel, Maximilien Martinez, Franck Coste, Kang Zhu, Rebecca Smith, Anna Georgina Kopasz, Yang Lu, Nicolas Bigot, Catherine Chapuis, Romane Riou, Nina Đukić, Stéphane Goffinont, Valentin Pressoir, Sara Patačko, Gyula Timinszky, Marc Delarue, Bertrand Castaing, Dragana Ahel, Andreja Mikoč, Sébastien Huet, Ivan Ahel, Marcin J. Suskiewicz
Sirtuins are an ancient family of enzymes with diverse nicotinamide adenine dinucleotide (NAD)-dependent activities. Here we identify family with sequence similarity 118 member B (FAM118B) and FAM118A—two understudied vertebrate proteins—as vertebrate-specific sirtuins with similarities to bacterial antiphage sirtuins. We show that human FAM118B forms head-to-tail filaments both in vitro and in living human cells, a feature that appears to be conserved in both FAM118B and its paralog FAM118A across vertebrates. While human FAM118B and FAM118A have individually very weak NAD-processing activity in vitro, their interaction leads to markedly increased activity, suggesting a tightly regulated system. The overexpression of wild-type human FAM118B and FAM118A leads to strongly decreased NAD levels in human cells, an effect that is abolished in catalytically dead or filament-deficient mutants. Our study highlights filament formation and NAD processing as conserved mechanisms among immunity-associated sirtuins across evolution. Baretić and Missoury et al. identify vertebrate proteins FAM118B and FAM118A as sirtuins similar to bacterial antiphage enzymes and show that FAM118A/B processing of NAD involves head-to-tail filament formation and a partnership between the two paralogs.
{"title":"Filament formation and NAD processing by noncanonical human FAM118 sirtuins","authors":"Domagoj Baretić, Sophia Missoury, Karishma Patel, Maximilien Martinez, Franck Coste, Kang Zhu, Rebecca Smith, Anna Georgina Kopasz, Yang Lu, Nicolas Bigot, Catherine Chapuis, Romane Riou, Nina Đukić, Stéphane Goffinont, Valentin Pressoir, Sara Patačko, Gyula Timinszky, Marc Delarue, Bertrand Castaing, Dragana Ahel, Andreja Mikoč, Sébastien Huet, Ivan Ahel, Marcin J. Suskiewicz","doi":"10.1038/s41594-025-01715-1","DOIUrl":"10.1038/s41594-025-01715-1","url":null,"abstract":"Sirtuins are an ancient family of enzymes with diverse nicotinamide adenine dinucleotide (NAD)-dependent activities. Here we identify family with sequence similarity 118 member B (FAM118B) and FAM118A—two understudied vertebrate proteins—as vertebrate-specific sirtuins with similarities to bacterial antiphage sirtuins. We show that human FAM118B forms head-to-tail filaments both in vitro and in living human cells, a feature that appears to be conserved in both FAM118B and its paralog FAM118A across vertebrates. While human FAM118B and FAM118A have individually very weak NAD-processing activity in vitro, their interaction leads to markedly increased activity, suggesting a tightly regulated system. The overexpression of wild-type human FAM118B and FAM118A leads to strongly decreased NAD levels in human cells, an effect that is abolished in catalytically dead or filament-deficient mutants. Our study highlights filament formation and NAD processing as conserved mechanisms among immunity-associated sirtuins across evolution. Baretić and Missoury et al. identify vertebrate proteins FAM118B and FAM118A as sirtuins similar to bacterial antiphage enzymes and show that FAM118A/B processing of NAD involves head-to-tail filament formation and a partnership between the two paralogs.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2526-2541"},"PeriodicalIF":10.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01715-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531502","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}
Pub Date : 2025-11-17DOI: 10.1038/s41594-025-01689-0
Helin Elhan, Alicia Damm, Justin L. Korfhage, Daniel Álvarez, Mehdi Zouiouich, Francesca Giordano, Stefano Vanni, Thomas J. Melia, Abdou Rachid Thiam
Lipid droplet (LD) growth mechanisms and the roles of LD-associated lipid transfer proteins remain poorly understood. Here we show that the autophagy lipid transfer protein ATG2A has an anabolic role and promotes LD expansion by transferring diacylglycerol (DAG), triacylglycerol (TAG) and phosphatidic acid, from the endoplasmic reticulum to LDs. In ATG2A deficiency, synthesized lipids are incorporated inefficiently into LDs and assemble new LDs. In addition, DAG O-acyltransferase 2 (DGAT2), which synthesizes TAG and expands LD, fails to relocate to LDs. In vitro, DAG recruits DGAT2 to LDs. These findings support the idea that ATG2A-mediated DAG transfer recruits DGAT2 to LDs, promoting LD expansion. ATG2A alone promotes LD growth by transferring TAG and DAG, but its effectiveness in LD expansion is reduced when DGAT2 is inhibited. This synergistic action with DGAT2 prevents the buildup of nonmembrane lipids within the endoplasmic reticulum and favors TAG synthesis on the LD surface. Elhan et al. show that ATG2A acts with DGAT2, the enzyme producing triacylglycerol (TAG), in lipid droplet growth. By delivering diacylglycerol to lipid droplets, ATG2A not only fuels TAG production but also promotes the recruitment of DGAT2 to droplet surfaces.
脂滴（LD）的生长机制和LD相关的脂质转移蛋白的作用仍然知之甚少。本研究表明，自噬脂质转移蛋白ATG2A具有合成代谢作用，通过将二酰基甘油（DAG）、三酰基甘油（TAG）和磷脂酸从内质网转移到LD，促进LD扩张。在ATG2A缺乏的情况下，合成的脂质不能有效地结合到ld中并组装新的ld。此外，合成TAG并扩展LD的DAG o -酰基转移酶2 （DGAT2）无法迁移到LD上。在体外，DAG将DGAT2招募到ld。这些发现支持了atg2a介导的DAG转移将DGAT2招募到LD，促进LD扩展的观点。单独ATG2A通过转移TAG和DAG促进LD生长，但当DGAT2被抑制时，其对LD扩展的作用降低。这种与DGAT2的协同作用可防止内质网内非膜脂质的积聚，并有利于LD表面TAG的合成。Elhan等人的研究表明，在脂滴生长过程中，ATG2A与生成三酰甘油（TAG）的酶DGAT2共同作用。通过将二酰基甘油输送到脂滴，ATG2A不仅为TAG的产生提供燃料，而且还促进DGAT2在脂滴表面的招募。
{"title":"ATG2A-mediated DAG transfer recruits DGAT2 for lipid droplet growth","authors":"Helin Elhan, Alicia Damm, Justin L. Korfhage, Daniel Álvarez, Mehdi Zouiouich, Francesca Giordano, Stefano Vanni, Thomas J. Melia, Abdou Rachid Thiam","doi":"10.1038/s41594-025-01689-0","DOIUrl":"10.1038/s41594-025-01689-0","url":null,"abstract":"Lipid droplet (LD) growth mechanisms and the roles of LD-associated lipid transfer proteins remain poorly understood. Here we show that the autophagy lipid transfer protein ATG2A has an anabolic role and promotes LD expansion by transferring diacylglycerol (DAG), triacylglycerol (TAG) and phosphatidic acid, from the endoplasmic reticulum to LDs. In ATG2A deficiency, synthesized lipids are incorporated inefficiently into LDs and assemble new LDs. In addition, DAG O-acyltransferase 2 (DGAT2), which synthesizes TAG and expands LD, fails to relocate to LDs. In vitro, DAG recruits DGAT2 to LDs. These findings support the idea that ATG2A-mediated DAG transfer recruits DGAT2 to LDs, promoting LD expansion. ATG2A alone promotes LD growth by transferring TAG and DAG, but its effectiveness in LD expansion is reduced when DGAT2 is inhibited. This synergistic action with DGAT2 prevents the buildup of nonmembrane lipids within the endoplasmic reticulum and favors TAG synthesis on the LD surface. Elhan et al. show that ATG2A acts with DGAT2, the enzyme producing triacylglycerol (TAG), in lipid droplet growth. By delivering diacylglycerol to lipid droplets, ATG2A not only fuels TAG production but also promotes the recruitment of DGAT2 to droplet surfaces.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2601-2613"},"PeriodicalIF":10.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01689-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531500","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}
Pub Date : 2025-11-17DOI: 10.1038/s41594-025-01714-2
Li Mi, Yu-Xuan Li, Xinchen Lv, Zi-Li Wan, Xu Liu, Kairan Zhang, Huican Li, Yue Yao, Leping Zhang, Zhe Xu, Xingyu Zhuang, Kunqian Ji, Min Jiang, Yangming Wang, Peilong Lu
Bystander editing remains a major limitation of current base editors, hindering their precision and therapeutic potential. Here, we present a de novo protein design strategy that creates a structurally rigid interface between a DNA-binding TALE domain and a cytosine deaminase, forming a unified editing module termed TALE-oriented deaminase (TOD). Cryo-EM analysis of TOD–DNA complexes confirms that this precise spatial architecture tightly restricts the deaminase activity window, thereby minimizing unwanted deamination. To further enhance editing specificity, we develop a split version, termed DdCBE–TOD, which virtually eliminates off-target editing. As a proof of concept, we apply DdCBE–TOD to generate a mitochondrial disease mouse model and to correct a pathogenic mutation associated with MERRF syndrome in patient-derived cells, achieving single-nucleotide precision. This work introduces a generalizable and computationally guided approach for ultra-precise base editing, offering a promising platform for both mechanistic studies and therapeutic correction of single-nucleotide mutations. Mi et al. use de novo protein design to address bystander and off-target editing in base editing, resulting in a highly precise mitochondrial cytosine base editor that is valuable for studying and treating mitochondrial diseases.
{"title":"Computational design of a high-precision mitochondrial DNA cytosine base editor","authors":"Li Mi, Yu-Xuan Li, Xinchen Lv, Zi-Li Wan, Xu Liu, Kairan Zhang, Huican Li, Yue Yao, Leping Zhang, Zhe Xu, Xingyu Zhuang, Kunqian Ji, Min Jiang, Yangming Wang, Peilong Lu","doi":"10.1038/s41594-025-01714-2","DOIUrl":"10.1038/s41594-025-01714-2","url":null,"abstract":"Bystander editing remains a major limitation of current base editors, hindering their precision and therapeutic potential. Here, we present a de novo protein design strategy that creates a structurally rigid interface between a DNA-binding TALE domain and a cytosine deaminase, forming a unified editing module termed TALE-oriented deaminase (TOD). Cryo-EM analysis of TOD–DNA complexes confirms that this precise spatial architecture tightly restricts the deaminase activity window, thereby minimizing unwanted deamination. To further enhance editing specificity, we develop a split version, termed DdCBE–TOD, which virtually eliminates off-target editing. As a proof of concept, we apply DdCBE–TOD to generate a mitochondrial disease mouse model and to correct a pathogenic mutation associated with MERRF syndrome in patient-derived cells, achieving single-nucleotide precision. This work introduces a generalizable and computationally guided approach for ultra-precise base editing, offering a promising platform for both mechanistic studies and therapeutic correction of single-nucleotide mutations. Mi et al. use de novo protein design to address bystander and off-target editing in base editing, resulting in a highly precise mitochondrial cytosine base editor that is valuable for studying and treating mitochondrial diseases.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2575-2586"},"PeriodicalIF":10.1,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145531501","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}
Pub Date : 2025-11-13DOI: 10.1038/s41594-025-01727-x
Participation in peer review is essential training for all scientists. We are now offering all Nature Structural & Molecular Biology reviewers the opportunity to invite an early career researcher to formally co-review manuscripts with them.
{"title":"Peer review for early career researchers","authors":"","doi":"10.1038/s41594-025-01727-x","DOIUrl":"10.1038/s41594-025-01727-x","url":null,"abstract":"Participation in peer review is essential training for all scientists. We are now offering all Nature Structural & Molecular Biology reviewers the opportunity to invite an early career researcher to formally co-review manuscripts with them.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 11","pages":"2131-2131"},"PeriodicalIF":10.1,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-025-01727-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509016","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}
Glucose-6-phosphate (G6P) transporters are crucial for glucose metabolism by mediating G6P transport from the cytoplasm to endoplasmic reticulum (ER). However, their transport mechanisms remain poorly understood. Here, we elucidate the structural and functional basis of human solute carrier family 37 member 2 (SLC37A2), a G6P transporter implicated in metabolic regulation and macrophage inflammation. We show that SLC37A2 functions as a uniporter, facilitating G6P transport independent of inorganic phosphate gradients. Structures of SLC37A2 in the apo and G6P-bound states reveal a dimeric architecture. Both the ER luminal-open and cytosolic-open structures are captured, showing the structural dynamics during G6P transport. G6P is coordinated by SLC37A2 through interactions with its phosphate and hydroxyl groups. Furthermore, mapping mutations associated with glycogen storage disease type Ib onto SLC37A2 highlights residues essential for transport activity. Together, this work provides structural insights into G6P transport and establishes a framework for understanding related metabolic disorders. Lai and Xu et al. used cryo-electron microscopy and functional analyses to elucidate the glucose-6-phosphate uniport mechanism of human solute carrier family 37 member 2 and its structural dynamics, offering insights into glucose metabolism and related disorders.
{"title":"Structural basis of glucose-6-phosphate transport by human SLC37A2","authors":"Qinxuan Lai, Mengzhen Xu, Yongxiang Gao, Zhisen Yang, Linfeng Sun, Xin Liu","doi":"10.1038/s41594-025-01712-4","DOIUrl":"10.1038/s41594-025-01712-4","url":null,"abstract":"Glucose-6-phosphate (G6P) transporters are crucial for glucose metabolism by mediating G6P transport from the cytoplasm to endoplasmic reticulum (ER). However, their transport mechanisms remain poorly understood. Here, we elucidate the structural and functional basis of human solute carrier family 37 member 2 (SLC37A2), a G6P transporter implicated in metabolic regulation and macrophage inflammation. We show that SLC37A2 functions as a uniporter, facilitating G6P transport independent of inorganic phosphate gradients. Structures of SLC37A2 in the apo and G6P-bound states reveal a dimeric architecture. Both the ER luminal-open and cytosolic-open structures are captured, showing the structural dynamics during G6P transport. G6P is coordinated by SLC37A2 through interactions with its phosphate and hydroxyl groups. Furthermore, mapping mutations associated with glycogen storage disease type Ib onto SLC37A2 highlights residues essential for transport activity. Together, this work provides structural insights into G6P transport and establishes a framework for understanding related metabolic disorders. Lai and Xu et al. used cryo-electron microscopy and functional analyses to elucidate the glucose-6-phosphate uniport mechanism of human solute carrier family 37 member 2 and its structural dynamics, offering insights into glucose metabolism and related disorders.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"112-122"},"PeriodicalIF":10.1,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492637","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}
Glycogen storage disease type Ib (GSD-Ib), caused by loss-of-function mutations in the endoplasmic reticulum transporter SLC37A4, disrupts glucose homeostasis through impaired glucose-6-phosphate (G6P)/phosphate (Pi) antiport. Despite its central role in glycogen metabolism and immune regulation, the structural mechanisms governing SLC37A4’s transport cycle and pathological dysfunction remain elusive. Here we report cryo-electron microscopy structures of human SLC37A4 in four functional states, capturing conformational transitions between lumen-facing and cytoplasm-facing states. Combined with mutational analysis, molecular dynamics simulations and functional assays, we identify a conserved substrate-binding pocket that alternately accommodates G6P and Pi through electrostatic complementarity and domain-dependent interactions. We further demonstrate that the high-affinity inhibitor S-4048 sterically occludes the cytoplasmic entry pathway by trapping the transporter in a cytoplasm-facing conformation. Our work elucidates the molecular pathology of GSD-Ib-linked mutations and provides a structural framework for developing therapies targeting this transporter in metabolic diseases. Zhou et al. report cryo-electron microscopy structures of human SLC37A4 in four states, elucidating conformational transitions during glucose-6-phosphate/phosphate transport and S-4048 inhibition. This study links structural mechanisms to glycogen storage disease type Ib pathology, offering therapeutic insights.
{"title":"Structural basis of G6P/Pi transport and inhibition in SLC37A4","authors":"Dong Zhou, Yang Zhang, Nanhao Chen, Shitang Huang, Chen Song, Zhe Zhang","doi":"10.1038/s41594-025-01711-5","DOIUrl":"10.1038/s41594-025-01711-5","url":null,"abstract":"Glycogen storage disease type Ib (GSD-Ib), caused by loss-of-function mutations in the endoplasmic reticulum transporter SLC37A4, disrupts glucose homeostasis through impaired glucose-6-phosphate (G6P)/phosphate (Pi) antiport. Despite its central role in glycogen metabolism and immune regulation, the structural mechanisms governing SLC37A4’s transport cycle and pathological dysfunction remain elusive. Here we report cryo-electron microscopy structures of human SLC37A4 in four functional states, capturing conformational transitions between lumen-facing and cytoplasm-facing states. Combined with mutational analysis, molecular dynamics simulations and functional assays, we identify a conserved substrate-binding pocket that alternately accommodates G6P and Pi through electrostatic complementarity and domain-dependent interactions. We further demonstrate that the high-affinity inhibitor S-4048 sterically occludes the cytoplasmic entry pathway by trapping the transporter in a cytoplasm-facing conformation. Our work elucidates the molecular pathology of GSD-Ib-linked mutations and provides a structural framework for developing therapies targeting this transporter in metabolic diseases. Zhou et al. report cryo-electron microscopy structures of human SLC37A4 in four states, elucidating conformational transitions during glucose-6-phosphate/phosphate transport and S-4048 inhibition. This study links structural mechanisms to glycogen storage disease type Ib pathology, offering therapeutic insights.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 1","pages":"123-133"},"PeriodicalIF":10.1,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145492636","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}
Pub Date : 2025-11-11DOI: 10.1038/s41594-025-01719-x
Benjamin Lang, Bálint Mészáros, Besian I. Sejdiu, Jaimin Patel, M. Madan Babu
Accurate prediction of protein structures is essential for understanding biological functions and guiding biomedical research. However, maintaining synchronization between structure models and rapidly expanding, continuously evolving protein sequence databases remains a major challenge. Here, we present AlphaSync ( alphasync.stjude.org ), a comprehensive resource that complements the AlphaFold Protein Structure Database. AlphaSync currently provides 2.6 million UniProt-synchronized structural models, including predictions for 40,016 updated proteins and isoforms from 925 species. AlphaSync achieves complete, up-to-date proteome coverage for 42 species, including humans, key pathogens and model organisms. It also provides residue-level annotations such as solvent accessibility, dihedral angles, intrinsic disorder status and over 4.7 billion atom-level noncovalent contacts. Its up-to-date structural models and detailed annotations will facilitate the study of protein structure–function relationships, assessment of sequence variants and machine learning tasks including protein design. With an intuitive web interface and application programming interface, AlphaSync enables protein research at scale and in detail. AlphaSync synchronizes AlphaFold Protein Structure Database predictions with UniProt sequences, providing up-to-date protein structures with residue-level annotations for humans, model organisms and pathogens through an accessible web interface and application programming interface.
{"title":"AlphaSync is an enhanced AlphaFold structure database synchronized with UniProt","authors":"Benjamin Lang, Bálint Mészáros, Besian I. Sejdiu, Jaimin Patel, M. Madan Babu","doi":"10.1038/s41594-025-01719-x","DOIUrl":"10.1038/s41594-025-01719-x","url":null,"abstract":"Accurate prediction of protein structures is essential for understanding biological functions and guiding biomedical research. However, maintaining synchronization between structure models and rapidly expanding, continuously evolving protein sequence databases remains a major challenge. Here, we present AlphaSync ( alphasync.stjude.org ), a comprehensive resource that complements the AlphaFold Protein Structure Database. AlphaSync currently provides 2.6 million UniProt-synchronized structural models, including predictions for 40,016 updated proteins and isoforms from 925 species. AlphaSync achieves complete, up-to-date proteome coverage for 42 species, including humans, key pathogens and model organisms. It also provides residue-level annotations such as solvent accessibility, dihedral angles, intrinsic disorder status and over 4.7 billion atom-level noncovalent contacts. Its up-to-date structural models and detailed annotations will facilitate the study of protein structure–function relationships, assessment of sequence variants and machine learning tasks including protein design. With an intuitive web interface and application programming interface, AlphaSync enables protein research at scale and in detail. AlphaSync synchronizes AlphaFold Protein Structure Database predictions with UniProt sequences, providing up-to-date protein structures with residue-level annotations for humans, model organisms and pathogens through an accessible web interface and application programming interface.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"32 12","pages":"2628-2632"},"PeriodicalIF":10.1,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484903","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：