Nature Structural &Molecular Biology最新文献

Molecular architecture and spatial organization of proteasomes in the human sperm nucleus. 人类精子核中蛋白酶体的分子结构和空间组织。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-09-01 DOI: 10.1038/s41594-026-01870-z

Piotr Kolata, Ália Dos Santos, Oliver Knowles, Tom Dendooven, Matteo Allegretti

{"title":"Molecular architecture and spatial organization of proteasomes in the human sperm nucleus.","authors":"Piotr Kolata, Ália Dos Santos, Oliver Knowles, Tom Dendooven, Matteo Allegretti","doi":"10.1038/s41594-026-01870-z","DOIUrl":"10.1038/s41594-026-01870-z","url":null,"abstract":"Proteasomes are fundamental for protein homeostasis and genome integrity and essential in spermatogenesis and fertilization. However, their presence, composition and role within the sperm nucleus are a subject of debate. Here we use in situ cryo-electron tomography in human sperm cells to elucidate the molecular architecture of nuclear proteasomes, which cluster in DNA-free, nuclear cavities within the sperm nucleus. We show that the main population of proteasomes consists of 20S core particles, with a smaller fraction of 20S capped by PA200 activator. Using single-particle cryo-electron microscopy of purified native human sperm proteasomes, we elucidate the features of the essential testis-specific subunit α4s, reporting the presence of a unique splice variant. We resolve a native peptide in the catalytic β2 subunit, providing insight into the proteolysis mechanism and PA200-mediated enhancement of trypsin activity. We show nuclear enrichment of proteasomes during sperm-cell differentiation in human testis tissue, with 20S and PA200 clustering following meiosis, at the spermatid stage. Our findings shed light on the organization and compositional diversity of nuclear proteasomes in human sperm cells, as well as their catalytic function.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875517","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

Repositioning of polyubiquitin alters the pathologic tau filament structure. 多泛素的重新定位改变了病理性的tau丝结构。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-08-31 DOI: 10.1038/s41594-026-01879-4

Ryohei Watanabe, Benjamin C Creekmore, Nabil F Darwich, Courtney L Smith, Hong Xu, Angelina Baltazar, Sacha Salphati, Lakshmi Changolkar, Kevt'her Hoxha, Bin Zhang, Caroline M O'Rourke, George M Burslem, Virginia M-Y Lee, Yi-Wei Chang, Edward B Lee

{"title":"Repositioning of polyubiquitin alters the pathologic tau filament structure.","authors":"Ryohei Watanabe, Benjamin C Creekmore, Nabil F Darwich, Courtney L Smith, Hong Xu, Angelina Baltazar, Sacha Salphati, Lakshmi Changolkar, Kevt'her Hoxha, Bin Zhang, Caroline M O'Rourke, George M Burslem, Virginia M-Y Lee, Yi-Wei Chang, Edward B Lee","doi":"10.1038/s41594-026-01879-4","DOIUrl":"https://doi.org/10.1038/s41594-026-01879-4","url":null,"abstract":"Structurally diverse tau filaments form proteinaceous aggregates in a heterogeneous group of neurodegenerative diseases called tauopathies. The factors extrinsic to the highly ordered core structure that influence tau filament stability are not well understood. Here, we found that polyubiquitinated tau filaments from Alzheimer disease and vacuolar tauopathy human brain tissue exhibit distinct seeding patterns in mice, in association with differences in tau filament ultrastructure determined by cryo-electron microscopy. Chemical modulation of the polarity of polyubiquitin adjacent to the tau core with the small molecule ubistatin B resulted in the repositioning of poorly structured densities toward positively charged residues on the highly structured core filament, leading to shifting of the protofilament-protofilament interface of certain vacuolar tauopathy tau filaments. These results suggest that the structure of tau filaments that are associated with different seeding activities in vivo can be influenced by post-translational modifications.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148866019","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

A single-amino-acid cleavage controls global mitochondrial complex integrity. 单氨基酸切割控制着整个线粒体复合体的完整性。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-08-31 DOI: 10.1038/s41594-026-01876-7

Cansu Kücükköse, Marcin Luzarowski, Fabian Stockert, Annette Flotho, Miguel Cosenza-Contreras, Fatih Demir, Max Gilbert, Jörn Dengjel, Friedel Drepper, Mandy Jeske, Hans-Georg Koch, Pitter F Huesgen, F-Nora Vögtle

引用次数: 0

HUNTER catches N-terminal prey of ICP55 in the mitochondria. HUNTER在线粒体中捕获ICP55的n端猎物。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-08-31 DOI: 10.1038/s41594-026-01872-x

Jiwoong Kang, Hyun-Woo Rhee

引用次数: 0

Structural and mechanistic insights into gating and allosteric modulation of GluN1-GluN3A NMDA receptors. GluN1-GluN3A NMDA受体门控和变构调节的结构和机制研究。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-08-28 DOI: 10.1038/s41594-026-01866-9

Junhoe Kim, Avery J Benton, James S Lotti, Nirvan Rouzbeh, Kasper B Hansen, Eric Gouaux

{"title":"Structural and mechanistic insights into gating and allosteric modulation of GluN1-GluN3A NMDA receptors.","authors":"Junhoe Kim, Avery J Benton, James S Lotti, Nirvan Rouzbeh, Kasper B Hansen, Eric Gouaux","doi":"10.1038/s41594-026-01866-9","DOIUrl":"https://doi.org/10.1038/s41594-026-01866-9","url":null,"abstract":"N-methyl-D-aspartate receptors (NMDARs) mediate excitatory signaling essential for synaptic plasticity and memory. Unlike GluN2-containing NMDARs, GluN3-containing receptors are activated solely by glycine and exhibit profound desensitization and paradoxical potentiation by GluN1-selective antagonists, including CGP-78608 (CGP). Although GluN3A-containing NMDARs regulate synapse pruning and excitotoxicity, and are associated with schizophrenia, autism and stroke, their native stoichiometry and gating mechanism are poorly defined. Here, using single-molecule pull-down analysis, we show that native GluN3A-containing receptors are diheteromeric assemblies. Cryogenic-electron microscopy analysis of GluN1-GluN3A receptors in antagonist-bound, preactive, active and desensitized states, augmented by electrophysiology and pharmacology experiments, show how glycine activates the receptor solely via GluN3A-dependent conformational changes, opening the gate with two-fold symmetry, and induces a roughly four-fold symmetric desensitized state. CGP-bound GluN1 restricts GluN3A rotation, promoting glycine-induced activation by blocking desensitization. These findings illuminate how CGP potentiates GluN1-GluN3A receptor activity, place the receptor gating mechanism on a structural foundation and define the molecular basis for pharmacological modulation.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851011","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

Universal pipeline for high-resolution GPCR structure determination. 用于高分辨率GPCR结构测定的通用管道。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-08-28 DOI: 10.1038/s41594-026-01869-6

Asato Kojima, Kouki Kawakami, Naoya Kobayashi, Kazuhiro Kobayashi, Toshiki E Matsui, Kohei Uemoto, Yuzhong Gu, Tomohiro J Narita, Mai Kugawa, Masahiro Fukuda, Hideaki E Kato

{"title":"Universal pipeline for high-resolution GPCR structure determination.","authors":"Asato Kojima, Kouki Kawakami, Naoya Kobayashi, Kazuhiro Kobayashi, Toshiki E Matsui, Kohei Uemoto, Yuzhong Gu, Tomohiro J Narita, Mai Kugawa, Masahiro Fukuda, Hideaki E Kato","doi":"10.1038/s41594-026-01869-6","DOIUrl":"https://doi.org/10.1038/s41594-026-01869-6","url":null,"abstract":"G protein-coupled receptors (GPCRs) regulate human physiology and are major drug targets. Although cryo-electron microscopy has accelerated GPCR structural biology, inactive-state structures remain difficult because current fusion-based strategies often require extensive experimental screening to identify rigid constructs suitable for high-resolution reconstruction. Here we introduce a universal pipeline that integrates an in silico fusion construct screening program, NOAH (nonexperimental, artificial-intelligence-assisted, high-throughput construct screening for structural analysis), with a de novo designed fusion protein, ARK1 (artificially designed fiducial marker). NOAH enabled structure determination of vasopressin V2 receptor bound to the antagonist tolvaptan or partial agonist OPC51803 and bradykinin B2 receptor bound to the antagonist icatibant, revealing receptor activation and inhibition mechanisms. Coupling NOAH to ARK1 improved the V2 receptor-tolvaptan map and enabled high-resolution structures of lysophosphatidic acid receptor 2 bound to Ki16425 and free fatty acid receptor 2 bound to GLPG0974. NOAH-ARK1 minimizes trial-and-error construct optimization and provides a broadly applicable route for GPCR structural analysis and drug discovery.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851014","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

Characterizing dynamics of productive dynein stepping by MINFLUX. 用MINFLUX表征生产动力步进动力学。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-08-26 DOI: 10.1038/s41594-026-01873-w

Joseph Slivka, Emma S Gleave-Hanford, Mert Golcuk, Devinda P Wijewardena, John T Canty, Paul R Selvin, Mert Gur, Andrew P Carter, Ahmet Yildiz

{"title":"Characterizing dynamics of productive dynein stepping by MINFLUX.","authors":"Joseph Slivka, Emma S Gleave-Hanford, Mert Golcuk, Devinda P Wijewardena, John T Canty, Paul R Selvin, Mert Gur, Andrew P Carter, Ahmet Yildiz","doi":"10.1038/s41594-026-01873-w","DOIUrl":"https://doi.org/10.1038/s41594-026-01873-w","url":null,"abstract":"Cytoplasmic dynein drives minus-end-directed motility along microtubules by converting ATP hydrolysis into coordinated structural changes but how this process produces directional stepping remains unresolved. The dynamics of dynein stepping have previously been characterized by tracking flexible regions of the motor with limited resolution. Here we site-specifically labeled the microtubule-binding domain of yeast dynein using a cysteine-light mutant and tracked stepping with submillisecond, nanometer precision at physiological ATP using minimal fluorescence photon flux (MINFLUX). We show that dynein hydrolyzes one ATP per step and moves in multiples of 8 nm. Steps are preceded by a transient plus-end-directed displacement ('dip'), corresponding to microtubule release upon ATP binding and diffusion of the stepping head around its partner. A slow ATP-hydrolyzing mutant shows more frequent dips, supporting a model in which ATP hydrolysis produces net forward movement. These results clarify the sequence of mechanochemical events underlying productive dynein stepping.","PeriodicalId":18836,"journal":{"name":"Nature Structural &Molecular Biology","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148830616","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

Unstructured but constructive FG repeats shape the nuclear pore complex architecture. 非结构化但建设性的FG重复形成核孔复杂结构。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-08-26 DOI: 10.1038/s41594-026-01868-7

Jonas S Fischer, Karsten Weis, Evgeny Onischenko

引用次数: 0

Molecular snapshots confirm ketamine's opioid nature. 分子快照证实了氯胺酮的阿片类性质。

IF 10.1 1区生物学

Nature Structural &Molecular Biology Pub Date : 2026-08-24 DOI: 10.1038/s41594-026-01874-9

Jordi Bonaventura, Michael Michaelides

引用次数: 0

Ion transport as a determinant of membrane fusion and fission. 离子传输作为膜融合和裂变的决定因素。