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| Open AccessSubstrate-induced condensation activates plant TIR domain proteins
Binding of the substrates NAD+ and ATP to the plant Toll/interleukin-1 receptor (TIR) domain proteins induces phase separation and, thereby, activation of TIR enzymatic and immune signalling activity.
- Wen Song
- , Li Liu
- & Jijie Chai
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Article
| Open AccessThe UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons
Attachment of the ubiquitin-like modifier UFM1 to 60S ribosomes has a critical function in the release and recycling of stalled or terminated ribosomes from the endoplasmic reticulum membrane.
- Linda Makhlouf
- , Joshua J. Peter
- & Yogesh Kulathu
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Article
| Open AccessCryo-EM structures of PP2A:B55–FAM122A and PP2A:B55–ARPP19
Cryo-electron microscopy structures of the PP2A:B55 holoenzyme bound to its inhibitors ARPP19 and FAM122A show distinct binding modes of the two inhibitors.
- Sathish K. R. Padi
- , Margaret R. Vos
- & Wolfgang Peti
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| Open AccessAntiviral type III CRISPR signalling via conjugation of ATP and SAM
The Bacteroides fragilis type III CRISPR protein Cmr conjugates ATP to S-adenosyl methionine, generating S-adenosyl methionine (SAM)-AMP, a novel second messenger with a role in antiviral signalling.
- Haotian Chi
- , Ville Hoikkala
- & Malcolm F. White
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Article
| Open AccessStructures illustrate step-by-step mitochondrial transcription initiation
A cryogenic electron microscopy study presents structures characterizing the initiation of RNA synthesis by yeast mitochondrial RNA polymerase at single-nucleotide addition steps.
- Quinten Goovaerts
- , Jiayu Shen
- & Kalyan Das
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Article
| Open AccessFrom primordial clocks to circadian oscillators
X-ray, cryo-EM and kinetic studies of the circadian oscillator KaiBC from the photosynthetic bacterium Rhodobacter sphaeroides shed light on the evolution of self-regulating oscillators.
- Warintra Pitsawong
- , Ricardo A. P. Pádua
- & Dorothee Kern
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Article
| Open AccessStructural basis for bacterial energy extraction from atmospheric hydrogen
Structural and biochemical studies of the Mycobacterium smegmatis hydrogenase Huc provides insights into how [NiFe] hydrogenases oxidize trace amounts of atmospheric hydrogen and transfer the electrons liberated via quinone transport.
- Rhys Grinter
- , Ashleigh Kropp
- & Chris Greening
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Structural basis for substrate selection by the SARS-CoV-2 replicase
Cryo-EM is used to visualize the SARS-CoV-2 RTC bound to each of the natural NTPs as well as remdesivir triphosphate (RDV-TP) in states poised for incorporation, explaining the interactions required for NTP recognition and RDV-TP selectivity.
- Brandon F. Malone
- , Jason K. Perry
- & Seth A. Darst
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Article
| Open AccessStructural basis of broad-spectrum β-lactam resistance in Staphylococcus aureus
Cryo-electron microscopy structures of Staphylococcus aureus BlaR1 reveal dynamic signalling states regulating broad spectrum β-lactam antibiotic resistance through cleavage of the transcriptional repressor BlaI and induced expression of the β-lactamase blaZ and the β-lactam-resistant cell-wall transpeptidase mecA.
- J. Andrew N. Alexander
- , Liam J. Worrall
- & Natalie C. J. Strynadka
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Article
| Open AccessRNA targeting unleashes indiscriminate nuclease activity of CRISPR–Cas12a2
Structural analysis of Cas12a2, a CRISPR-associated nuclease that nonspecifically cleaves ssRNA, ssDNA and dsDNA, reveals a complete activation pathway involved in the abortive infection system protecting cells against invasion.
- Jack P. K. Bravo
- , Thomson Hallmark
- & David W. Taylor
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Article
| Open AccessStructure of the OMEGA nickase IsrB in complex with ωRNA and target DNA
The cryogenic-electron microscopy structure of the D. thermocuniculi IsrB protein in complex with its cognate ωRNA and a target DNA shows that the RNA-dominant IsrB effector complex shares a common scaffold with the protein-dominant Cas9 effector complex.
- Seiichi Hirano
- , Kalli Kappel
- & Feng Zhang
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A universal coupling mechanism of respiratory complex I
Cryo-electron microscopy studies of Escherichia coli complex I suggest a conserved mechanism of coupled proton transfers and electrostatic interactions that result in proton ejection from the complex exclusively at the distal NuoL subunit.
- Vladyslav Kravchuk
- , Olga Petrova
- & Leonid Sazanov
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Article
| Open AccessMechanism of AAA+ ATPase-mediated RuvAB–Holliday junction branch migration
Structures of the ATP-hydrolysing RuvAB complex captured in multiple conformations provide mechanistic insights into coordinated ATPase and motor activity during DNA recombination.
- Jiri Wald
- , Dirk Fahrenkamp
- & Thomas C. Marlovits
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Article
| Open AccessThe mechanism of RNA capping by SARS-CoV-2
Reconstitution of the SARS-CoV-2 RNA 5′ cap reveals the unconventional mechanism by which SARS-CoV-2 caps its RNA genome, providing a new target in the development of antiviral agents to treat COVID-19.
- Gina J. Park
- , Adam Osinski
- & Vincent S. Tagliabracci
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Article
| Open AccessA non-canonical vitamin K cycle is a potent ferroptosis suppressor
Biochemical and lipidomic analyses identify an anti-ferroptotic function of vitamin K and reveal ferroptosis suppressor protein 1 (FSP1) as the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle.
- Eikan Mishima
- , Junya Ito
- & Marcus Conrad
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Article
| Open AccessStructure of the MRAS–SHOC2–PP1C phosphatase complex
A structure of the MRAS–SHOC2–PP1C complex supports a RAS-driven and multi-molecular model for RAF activation in which individual RAS–GTP molecules recruit RAF–14-3-3 and SHOC2–PP1C to activate the downstream pathway.
- Zachary J. Hauseman
- , Michelle Fodor
- & Daniel A. King
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Mechanisms and inhibition of Porcupine-mediated Wnt acylation
Cryo-electron microscopy structures of human Porcupine in complex with palmitoleoyl-coenzyme A, the inhibitor LGK974 and its peptide substrate suggest a mechanism for Wnt acylation.
- Yang Liu
- , Xiaofeng Qi
- & Xiaochun Li
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Structures of the human CST-Polα–primase complex bound to telomere templates
A structural analysis demonstrates how the single-stranded DNA-binding accessory protein complex CST physically organizes the human DNA polymerase-α–primase complex for efficient primer synthesis during telomere replication.
- Qixiang He
- , Xiuhua Lin
- & Ci Ji Lim
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Article
| Open AccessDiscovery of non-squalene triterpenes
Chimeric triterpene synthases are identified that catalyse non-squalene-dependent triterpene biosynthesis.
- Hui Tao
- , Lukas Lauterbach
- & Tiangang Liu
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| Open AccessStructural basis for mismatch surveillance by CRISPR–Cas9
Cryo-electron microscopy structures of Cas9 during mismatch cleavage provide insight into the mechanisms that control off-target effects of Cas9, which will aid in the future design of high-fidelity Cas9 variants with reduced off-target cleavage.
- Jack P. K. Bravo
- , Mu-Sen Liu
- & David W. Taylor
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Structure determination of high-energy states in a dynamic protein ensemble
Combining NMR spectroscopy-derived pseudocontact shifts (PCSs) with Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion enables protein structure determination of lowly populated high-energy states that are essential for macromolecular function.
- John B. Stiller
- , Renee Otten
- & Dorothee Kern
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| Open AccessCrystallographic snapshots of a B12-dependent radical SAM methyltransferase
Structural and spectroscopic studies show how a B12-dependent radical SAM enzyme catalyses unique and challenging alkylation chemistry, including protein post-translational modification required for methane biosynthesis.
- Cameron D. Fyfe
- , Noelia Bernardo-García
- & Olivier Berteau
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Article
| Open AccessHELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51
HELQ is differentially regulated by RAD51, which stimulates helicase activity, and RPA, which inhibits helicase activity and stimulates annealing.
- Roopesh Anand
- , Erika Buechelmaier
- & Simon J. Boulton
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Activation mechanism of PINK1
Unphosphorylated PINK1 of Pediculus humanus corporis forms a dimerized state before undergoing trans-autophosphorylation, and phosphorylated PINK1 undergoes a conformational change in the N-lobe to produce its phosphorylated, ubiquitin-binding state.
- Zhong Yan Gan
- , Sylvie Callegari
- & David Komander
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β-NAD as a building block in natural product biosynthesis
β-Nicotinamide adenine dinucleotide is used as a building block in secondary metabolite biosynthetic pathways for a novel class of natural products.
- Lena Barra
- , Takayoshi Awakawa
- & Ikuro Abe
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The human microbiome encodes resistance to the antidiabetic drug acarbose
Bacteria in the human gut and oral microbiome encode enzymes that selectively phosphorylate the antidiabetic drug acarbose—an inhibitor of both human and bacterial α-glucosidases—resulting in its inactivation and limiting the drug's effects on the ability of the host to metabolize complex carbohydrates.
- Jared Balaich
- , Michael Estrella
- & Mohamed S. Donia
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Structural insights into Ubr1-mediated N-degron polyubiquitination
Structures of Ubr1 in complex with Ubc2, ubiquitin and two N-degron peptides reveal a Ubc2-binding region and an acceptor ubiquitin-binding loop on Ubr1, providing mechanistic insights into the initiation and elongation steps of ubiquitination catalysed by Ubr1.
- Man Pan
- , Qingyun Zheng
- & Minglei Zhao
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Structural basis of human separase regulation by securin and CDK1–cyclin B1
Structures of separase in complex with either securin or cyclin B–CDK1 shed light on the regulation of chromosome separation during the cell cycle.
- Jun Yu
- , Pierre Raia
- & Andreas Boland
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Structures of rhodopsin in complex with G-protein-coupled receptor kinase 1
Cryo-EM structures of complexes between GRK1 and rhodopsin shed light on how a small number of GRKs can selectively recognize and be activated by hundreds of different G-protein-coupled receptors.
- Qiuyan Chen
- , Manolo Plasencia
- & John J. G. Tesmer
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Article
| Open AccessStructural basis of early translocation events on the ribosome
Cryo-electron microscopy and single-molecule fluorescence methods are used to elucidate the mechanism of early translocation events on the bacterial ribosome.
- Emily J. Rundlet
- , Mikael Holm
- & Scott C. Blanchard
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Concerted cutting by Spo11 illuminates meiotic DNA break mechanics
A small proportion of Spo11-dependent DNA double-strand breaks are ‘double cuts’—adjacent breaks that occur in concert—revealing that gap repair during meiosis includes that of DNA gaps generated by Spo11 itself.
- Dominic Johnson
- , Margaret Crawford
- & Matthew J. Neale
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A lysine–cysteine redox switch with an NOS bridge regulates enzyme function
A NOS bridge between cysteine and lysine residues serves as an allosteric redox switch in the transaldolase enzyme of Neisseria gonorrhoeae, demonstrating the existence of protein regulatory switches that contain covalent crosslinks other than disulfides.
- Marie Wensien
- , Fabian Rabe von Pappenheim
- & Kai Tittmann
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Structure of human telomerase holoenzyme with bound telomeric DNA
A high-resolution structure of human telomerase bound to telomeric DNA reveals details of telomerase assembly and its active site, and sheds light on how mutations alter telomerase function.
- George E. Ghanim
- , Adam J. Fountain
- & Thi Hoang Duong Nguyen
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Structural insights into the inhibition of glycine reuptake
Serial synchrotron crystallography reveals the structure of the human glycine transporter GlyT1, showing how a state-specific inhibitor exerts its effects, and potentially informing the design of new GlyT1 inhibitors to treat a range of disorders of the central nervous system.
- Azadeh Shahsavar
- , Peter Stohler
- & Poul Nissen
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Structure of mycobacterial ATP synthase bound to the tuberculosis drug bedaquiline
Structures of Mycobacterium smegmatis ATP synthase provide insights into how the enzyme conserves energy by autoinhibition of ATP hydrolysis and the mechanism of action of bedaquiline, a drug used in treatment of multidrug-resistant tuberculosis.
- Hui Guo
- , Gautier M. Courbon
- & John L. Rubinstein
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Molecular dissection of amyloid disaggregation by human HSP70
The molecular steps that lead to the disaggregation of amyloid fibrils are shown to involve the synergistic action of HSP70 and its co-chaperones DNAJB1 and HSP110.
- Anne S. Wentink
- , Nadinath B. Nillegoda
- & Bernd Bukau
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Mechanism of strand exchange from RecA–DNA synaptic and D-loop structures
Cryo-electron microscopy structures of the bacterial recombination protein RecA with DNA, and of RecA–D-loop complexes, provide insights into the double-stranded DNA opening, homology search and strand-exchange processes of homologous recombination.
- Haijuan Yang
- , Chun Zhou
- & Nikola P. Pavletich
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An enzymatic Alder-ene reaction
Analysis of two homologous groups of fungal pericyclases demonstrates how they can catalyse either an Alder-ene reaction—which has not previously been found in nature—or a hetero-Diels–Alder reaction.
- Masao Ohashi
- , Cooper S. Jamieson
- & Yi Tang
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The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease
The IFITM3 innate immunity protein directly binds presenilin near the active site and upregulates γ-secretase activity and the production of amyloid-β, and IFITM3 is upregulated in patients with late-onset Alzheimer’s disease.
- Ji-Yeun Hur
- , Georgia R. Frost
- & Yue-Ming Li
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PCNA activates the MutLγ endonuclease to promote meiotic crossing over
A new mechanism explaining how double Holliday junctions are specifically resolved into crossovers during meiosis is shown that resembles the initiation of DNA mismatch repair.
- Dhananjaya S. Kulkarni
- , Shannon N. Owens
- & Neil Hunter
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Structural basis for dimerization quality control
Structural studies of the dimerization quality control E3 ubiquitin ligase SCF–FBXL17 indicate that its selectivity for aberrant complex formation is based on recognizing both shape and complementarity of interacting domains.
- Elijah L. Mena
- , Predrag Jevtić
- & Michael Rape
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Structure of the ER membrane complex, a transmembrane-domain insertase
The cryo-electron microscopy structure of the ER membrane complex provides insight into its overall architecture, evolution and function in co-translational protein insertion.
- Lin Bai
- , Qinglong You
- & Huilin Li
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Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme
Cryo-electron microscopy structures and functional and mutagenesis studies provide insights into the catalysis of triacylglycerol synthesis by human acyl-CoA diacylglycerol acyltransferase at its intramembrane active site.
- Xuewu Sui
- , Kun Wang
- & Robert V. Farese Jr
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Phase separation directs ubiquitination of gene-body nucleosomes
The yeast E3 ligase Bre1 forms a core–shell condensate with the scaffold protein Lge1, implicating liquid–liquid phase separation as a mechanism in the ubiquitination of histone H2B along gene bodies.
- Laura D. Gallego
- , Maren Schneider
- & Alwin Köhler
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Gene expression and cell identity controlled by anaphase-promoting complex
WDR5 and TBP recruit anaphase-promoting complex to specific transcription start sites in mitosis, initiating a ubiquitin-dependent mechanism that preserves cell identity by linking gene expression and cell division.
- Eugene Oh
- , Kevin G. Mark
- & Michael Rape
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Selective loading and processing of prespacers for precise CRISPR adaptation
Cas1–Cas2 selects precursor prespacers from DNA fragments in a length- and PAM-sequence-dependent manner, and these precursors are trimmed by DnaQ exonucleases to enable integration into the CRISPR locus in the correct orientation.
- Sungchul Kim
- , Luuk Loeff
- & Chirlmin Joo
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The structure of human thyroglobulin
The cryo-electron microscopy structure of human thyroglobulin reveals that proximity, flexibility and solvent exposure are key characteristics of its hormonogenic tyrosine pairs, and provides a framework for understanding the formation of thyroid hormones.
- Francesca Coscia
- , Ajda Taler-Verčič
- & Jan Löwe
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Mechanism of head-to-head MCM double-hexamer formation revealed by cryo-EM
Time-resolved electron microscopy reveals the mechanism by which the origin recognition complex loads pairs of MCM helicases around DNA prior to bidirectional replication.
- Thomas C. R. Miller
- , Julia Locke
- & Alessandro Costa
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Structures of a RAG-like transposase during cut-and-paste transposition
Analysis of multiple structures of the Helicoverpa zea DNA transposase Transib, determined by X-ray crystallography and cryo-electron microscopy, reveals the detailed pathway of the transposition reaction and sheds light on the evolution of the RAG recombinase.
- Chang Liu
- , Yang Yang
- & David G. Schatz