Nature Structural & Molecular Biology最新文献

Cracking the code of native amyloid fibrils: advances and next steps to enable pathology-informed therapeutic and diagnostic 破解天然淀粉样蛋白原纤维的代码：进展和下一步，使病理知情的治疗和诊断

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2026-04-20 DOI: 10.1038/s41594-026-01792-w

Hilal A. Lashuel

{"title":"Cracking the code of native amyloid fibrils: advances and next steps to enable pathology-informed therapeutic and diagnostic","authors":"Hilal A. Lashuel","doi":"10.1038/s41594-026-01792-w","DOIUrl":"10.1038/s41594-026-01792-w","url":null,"abstract":"Cryo-electron microscopy studies on amyloid fibrils formed by different proteins and isolated from the brains of persons with neurodegenerative diseases have consistently shown that their core structure is distinct from that of fibrils formed by the same proteins in cell-free systems. Attempts to replicate brain-derived amyloid fibrils in vitro have thus far fallen short of faithfully reproducing their structure, post-translational modifications and pathological properties. Whether this discrepancy is a major contributing factor to the poor clinical translation of antiamyloid therapies and diagnostics remains uncertain, partially because the structure of amyloid fibrils formed in the commonly used preclinical models remains unknown. This article presents (1) an overview of recent advances and progress toward reproducing disease-relevant pathological aggregates in vitro and in preclinical models of neurodegenerative diseases; (2) an experimental strategy to determine the structure of fibrils from these models; and (3) recommendations for optimizing their use to bridge the translational gap and support the development of more effective therapies. Establishing that the process of fibrillization and inclusion formation can be faithfully recapitulated in preclinical models is also crucial for enhancing their translational relevance and to guide the development of disease-relevant diagnostics and therapeutics. Until native fibrils can be produced at scale, the choice of which type of fibril preparation to use should be guided by the specific research question and intended application as different applications may warrant different levels of biochemical and structural similarity to disease-derived fibrils. Here, the author describes advances in understanding structures and post-translational modifications of amyloid fibrils through various techniques and the degree to which they recapitulate physiology and pathology, to better guide method selection when designing therapeutic or diagnostic interventions.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 4","pages":"567-576"},"PeriodicalIF":10.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721056","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}

引用次数: 0

Structural insights into coffee bitter taste perception by TAS2R43 receptor TAS2R43受体对咖啡苦味感知的结构研究

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2026-04-20 DOI: 10.1038/s41594-026-01776-w

Yoojoong Kim, Ryan H. Gumpper, Yuxuan Zhuang, Ron O. Dror, Bryan L. Roth

{"title":"Structural insights into coffee bitter taste perception by TAS2R43 receptor","authors":"Yoojoong Kim, Ryan H. Gumpper, Yuxuan Zhuang, Ron O. Dror, Bryan L. Roth","doi":"10.1038/s41594-026-01776-w","DOIUrl":"10.1038/s41594-026-01776-w","url":null,"abstract":"Bitter taste functions as a means of both protection against potentially toxic compounds and savoring bitter tasting foods and beverages. Among the 26 bitter taste receptors, taste receptor type 2 member 43 (TAS2R43) has been identified as key for recognizing the bitter taste of coffee. TAS2R43 has also been implicated in many other physiological processes, including the regulation of glucagon-like peptide 1 release from the intestine, bronchodilation, innate immunity and metabolism. Here we report cryo-electron microscopy structures of human TAS2R43 coupled with inhibitory G protein or gustducin (Ggust) stabilized by the potent nephrotoxin and carcinogen aristolochic acid I. Both structures revealed that aristolochic acid I binds in a presumed orthosteric pocket shared with other bitter taste receptor. Further structural, functional and computational studies revealed potential modes for coffee’s constituents including caffeine and cafestol, which are bitter tastants from coffee. Lastly, long-timescale molecular dynamics simulations identified potential cryptic allosteric pockets in TAS2R43. These structures could accelerate the search for specific bitter taste ligands that ultimately may be therapeutically useful. Kim et al. revealed how taste receptor type 2 member 43, a bitter taste receptor that detects coffee-derived compounds, recognizes bitter tastants through cryo-electron microscopy structures of ligand-bound complexes, supported by biochemical and computational analyses, providing a structural framework for coffee bitter taste signaling.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 4","pages":"701-710"},"PeriodicalIF":10.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01776-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721055","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}

引用次数: 0

Predicting RNA cellular activity 预测RNA细胞活性

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2026-04-20 DOI: 10.1038/s41594-026-01802-x

Sara Osman

引用次数: 0

Ligand binding modes of the bitter taste receptor T2R14 and T2R46 苦味受体T2R14和T2R46的配体结合模式

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2026-04-20 DOI: 10.1038/s41594-026-01786-8

Qiuxiang Tan, Yu Yu, Xuteng Han, Kezhen Liu, Shuo Han, Mu Wang, Yuan Wei, Yingrong Zhu, Qiuru Chen, Limin Ma, Cuiying Yi, Xiaojing Chu, Beili Wu, Qiang Zhao

{"title":"Ligand binding modes of the bitter taste receptor T2R14 and T2R46","authors":"Qiuxiang Tan, Yu Yu, Xuteng Han, Kezhen Liu, Shuo Han, Mu Wang, Yuan Wei, Yingrong Zhu, Qiuru Chen, Limin Ma, Cuiying Yi, Xiaojing Chu, Beili Wu, Qiang Zhao","doi":"10.1038/s41594-026-01786-8","DOIUrl":"10.1038/s41594-026-01786-8","url":null,"abstract":"Bitter taste receptors (T2Rs) are considered attractive drug targets. However, the ligand recognition and selectivity of these receptors remain elusive, hampering their drug development. Here we present seven structures of human T2R14 and T2R46 in apo or ligand-bound state. Combined with molecular docking and mutagenesis data, the structures reveal an extracellular ligand-binding site in T2R14 for most of its ligands, which is different from the intracellular binding site reported recently. In contrast, T2R46 exhibits a conserved binding pocket that accommodates various ligands with distinct interaction patterns. Furthermore, the second extracellular loop in T2R14 and T2R46 acts as a tethered agonist to potentially facilitate agonist response of these two receptors to the weak tastant agonists. These findings could accelerate drug discovery targeting T2Rs. Tan, Yu, Han et al. show how human bitter taste receptors recognize diverse ligands by determining several T2R structures. The study presents distinct binding modes and an intrinsic activation mechanism.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 4","pages":"691-700"},"PeriodicalIF":10.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01786-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147721054","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}

引用次数: 0

Many ligands and states of bitter taste GPCRs 许多配体和苦味gpcr的状态

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2026-04-20 DOI: 10.1038/s41594-026-01790-y

Evgenii Ziaikin, Nitsan Dallal, Masha Y. Niv

引用次数: 0

Calcium dependent activation of the TMEM16F scramblase and ion channel 钙依赖性激活TMEM16F超燃酶和离子通道。

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2026-04-17 DOI: 10.1038/s41594-026-01789-5

Zhang Feng, Omar E. Alvarenga, Eleonora Di Zanni, Sangyun Lee, George Khelashvili, Alessio Accardi

{"title":"Calcium dependent activation of the TMEM16F scramblase and ion channel","authors":"Zhang Feng, Omar E. Alvarenga, Eleonora Di Zanni, Sangyun Lee, George Khelashvili, Alessio Accardi","doi":"10.1038/s41594-026-01789-5","DOIUrl":"10.1038/s41594-026-01789-5","url":null,"abstract":"The ubiquitous transmembrane protein 16F (TMEM16F) Ca2+-activated channel and scramblase catalyzes phosphatidylserine externalization to enable blood coagulation, membrane fusion and brain immune surveillance. Despite its importance, the molecular mechanisms underlying TMEM16F activation remain poorly understood. Here, we obtained high-resolution cryo-electron microscopy structures of TMEM16F active in liposomes. In high-activity conditions, TMEM16F adopts two conformations, the canonical Ca2+-bound closed state and one where the upward rotation of the cytosolic domain leads to an X-shaped groove that forms a transmembrane pore and locally thins the membrane. Using mutagenesis, functional assays and molecular dynamics simulations, we show that the X-shaped groove is active and mediates nonselective ion flux and lipid scrambling through distinct pathways; ions move within the protein-delimited pore, whereas lipids skirt the X-shaped groove. Our findings provide a complete picture of TMEM16F Ca2+-dependent gating and demonstrate that imaging membrane proteins in a native-like environment can allow capturing otherwise inaccessible active states. Feng, Alvarenga et al. use cryo-electron microscopy to visualize the activation of the transmembrane protein 16F channel and scramblase in liposomes to show that it adopts a conformation that forms separate pathways for ions and lipids, thereby rationalizing its dual activity.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 4","pages":"664-676"},"PeriodicalIF":10.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01789-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147702106","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}

引用次数: 0

MitoPerturb-Seq identifies links between nuclear and mitochondrial genomes in single cells MitoPerturb-Seq鉴定单细胞中核基因组和线粒体基因组之间的联系。

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2026-04-09 DOI: 10.1038/s41594-026-01780-0

引用次数: 0

A two-step mechanism for sugar translocation 糖易位的两步机制

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2026-04-08 DOI: 10.1038/s41594-026-01784-w

Do-Hwan Ahn, Claudia Alleva, Tom Reichenbach, Ashutosh Gulati, Alessandro Ruda, Marta Bonaccorsi, Jakob M. Silberberg, Magnus Claesson, Albert Suades, Lucie Delemotte, Göran Widmalm, David Drew

{"title":"A two-step mechanism for sugar translocation","authors":"Do-Hwan Ahn, Claudia Alleva, Tom Reichenbach, Ashutosh Gulati, Alessandro Ruda, Marta Bonaccorsi, Jakob M. Silberberg, Magnus Claesson, Albert Suades, Lucie Delemotte, Göran Widmalm, David Drew","doi":"10.1038/s41594-026-01784-w","DOIUrl":"10.1038/s41594-026-01784-w","url":null,"abstract":"In mammals, glucose transporters (GLUTs) mediate organism-wide sugar distribution, yet the molecular basis of substrate specificity remains unclear. The bacterial xylose transporter XylE serves as a model for GLUTs. However, although xylose and glucose bind with a similar affinity, xylose is transported, but glucose acts as an inhibitor. Here, using saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, we distinguished transported sugars from sugar inhibitors. Our findings revealed that only transported sugars generate STD NMR signals, which are abolished for xylose when XylE is trapped in either outward- or inward-facing conformations. Engineering the sugar-binding pocket and gating helix TM7b enabled glucose transport by XylE and corresponding STD signals. Using complementary molecular dynamics simulations, together with structural, biochemical and STD NMR analysis of related parasitic and mammalian GLUTs, we identified TM7b as a key determinant of occluded state formation. We conclude that, rather than the initial substrate-binding event observed in experimental structures, formation of a substrate-induced transition-state intermediate is the primary determinant of specificity in transporters. Sugar porters are textbook examples of how transport activity is described by Michaelis–Menten kinetics. Here, using saturation transfer difference nuclear magnetic resonance spectroscopy, Ahn et al. conclude that the fully occluded state of a sugar transporter is analogous to the transition state in soluble enzymes.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 4","pages":"652-663"},"PeriodicalIF":10.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01784-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147631133","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}

引用次数: 0

Microtubules in the axon are GDP bound but adopt a stable GTP-like expanded state 轴突微管受GDP约束，但呈稳定的类似GDP的扩张状态

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2026-04-08 DOI: 10.1038/s41594-026-01787-7

Elena A. Zehr, Shufeng Sun, Stephanie L. Sarbanes, Antonina Roll-Mecak

{"title":"Microtubules in the axon are GDP bound but adopt a stable GTP-like expanded state","authors":"Elena A. Zehr, Shufeng Sun, Stephanie L. Sarbanes, Antonina Roll-Mecak","doi":"10.1038/s41594-026-01787-7","DOIUrl":"10.1038/s41594-026-01787-7","url":null,"abstract":"Microtubules scaffold cells, supporting signaling and cargo transport. They assemble from GTP–tubulin, which hydrolyzes to GDP–tubulin during polymerization. GTP–microtubule lattices are stable; GDP lattices depolymerize rapidly. In vitro, hydrolysis triggers lattice compaction. Lattice spacing regulates motors and microtubule-associated proteins; however, the conformation of tubulin in microtubules in cells is unknown. Here, we present the atomic-resolution cryo-electron microscopy structure of human microtubules in situ, in the axons of human cortical neurons derived from induced pluripotent stem cells (iPS cells). Our 2.7-Å-resolution reconstruction delineates bound water molecules and reveals that axonal microtubules adopt an expanded GTP-like lattice, despite being GDP bound. Using cryo-electron tomography and power spectrum analysis, we find that, unlike in axons, microtubules in undifferentiated iPS cells are compacted. Therefore, lattice expansion is part of neuronal differentiation. Our work provides molecular insights into neurogenesis and has implications for understanding microtubule stability and effector recruitment in neurons. Zehr et al. revealed the 2.7-Å cryo-electron microscopy reconstruction of human microtubules in situ in the axon of induced pluripotent stem cell (iPS cell)-derived neurons. It shows an expanded microtubule lattice yet bound to GDP, in contrast to the compacted lattice observed at the iPS cell stage.","PeriodicalId":49141,"journal":{"name":"Nature Structural & Molecular Biology","volume":"33 4","pages":"631-640"},"PeriodicalIF":10.1,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41594-026-01787-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147631131","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}

引用次数: 0

Challenges of studying signaling metabolites in early development 研究早期发育中信号代谢产物的挑战。

IF 10.1 1区生物学

Nature Structural & Molecular Biology Pub Date : 2026-04-06 DOI: 10.1038/s41594-026-01791-x

Gregg Duester

引用次数: 0