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| Open AccessInfluence of pump laser fluence on ultrafast myoglobin structural dynamics
Ultrafast time-resolved serial femtosecond crystallography is used to investigate a photodissociation reaction in a protein, revealing the strong impact of the pump laser fluence on the structural changes and the reaction mechanism.
- Thomas R. M. Barends
- , Alexander Gorel
- & Ilme Schlichting
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Article
| Open AccessThe CRISPR effector Cam1 mediates membrane depolarization for phage defence
The prokaryotic non-enzymatic effector protein Cam1 mediates CRISPR immunity by binding tetra-adenylate second messengers and forming a pore in the membrane that induces membrane depolarization and growth arrest.
- Christian F. Baca
- , You Yu
- & Luciano A. Marraffini
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Article
| Open AccessStructures, functions and adaptations of the human LINE-1 ORF2 protein
X-ray crystallography, cryo-electron microscopy, structural modelling, biochemistry, cell biology, and evolutionary analysis enable characterization of ORF2p, the reverse transcriptase of the ancient ‘parasitic’ LINE-1 retrotransposon that has written around one-third of the human genome.
- Eric T. Baldwin
- , Trevor van Eeuwen
- & Martin S. Taylor
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Article
| Open AccessStructural basis of Gabija anti-phage defence and viral immune evasion
X-ray crystallography, cryo-EM and biochemical analysis provide insight into the assembly of the bacterial Gabija complex, an anti-phage system, and reveal how viruses can evade this defence mechanism.
- Sadie P. Antine
- , Alex G. Johnson
- & Philip J. Kranzusch
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Recognition and maturation of IL-18 by caspase-4 noncanonical inflammasome
Activated human caspase-4 directly and efficiently processes IL-18 in vitro and during bacterial infections, cleaving the same tetrapeptide site in pro-IL-18 as caspase-1.
- Xuyan Shi
- , Qichao Sun
- & Feng Shao
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Article
| Open AccesspiRNA processing by a trimeric Schlafen-domain nuclease
The endoribonuclease PUCH, a trimer of Schlafen-like-domain proteins, initiates piRNA processing in the nematode Caenorhabditis elegans through 5′-end piRNA precursor cleavage.
- Nadezda Podvalnaya
- , Alfred W. Bronkhorst
- & René F. Ketting
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Intricate 3D architecture of a DNA mimic of GFP
X-ray crystallography and cryo-electron microscopy analyses of Lettuce—a DNA mimic of GFP—bound to various fluorophores reveal previously unknown structures of DNA that rival analogous RNAs in complexity.
- Luiz F. M. Passalacqua
- , Michael T. Banco
- & Adrian R. Ferré-D’Amaré
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Article
| Open AccessEnhanced rare-earth separation with a metal-sensitive lanmodulin dimer
A study biochemically and structurally characterizes a lanmodulin from Hansschlegelia quercus with an oligomeric state sensitive to rare-earth ionic radius.
- Joseph A. Mattocks
- , Jonathan J. Jung
- & Joseph A. Cotruvo Jr
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A small-molecule PI3Kα activator for cardioprotection and neuroregeneration
A new specific, small-molecule activator of the PI3Kα isoform (UCL-TRO-1938) identified through high-throughput screening can transiently activate PI3K signalling and biological responses in cells and tissues, with potential therapeutic applications in tissue protection and regeneration.
- Grace Q. Gong
- , Benoit Bilanges
- & Bart Vanhaesebroeck
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Article
| Open AccessStructural evidence for intermediates during O2 formation in photosystem II
Using serial femtosecond X-ray cystallography, we provide structural insights into the final reaction step of Kok’s photosynthetic water oxidation cycle, specifically the S3→[S4]→S0 transition where O2 is formed.
- Asmit Bhowmick
- , Rana Hussein
- & Vittal K. Yachandra
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Article
| Open AccessUltrafast structural changes direct the first molecular events of vision
One picosecond after photoactivation, isomerized retinal pulls away from half of its numerous interactions with its binding pocket, and the excess of the photon energy is released through an anisotropic protein breathing motion in the direction of the extracellular space.
- Thomas Gruhl
- , Tobias Weinert
- & Valerie Panneels
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Immunoglobulin M perception by FcμR
The structural basis for the molecular mechanism of recognition of different IgM forms by the IgM receptor FcμR is determined using crystallography and cryo-electron microscopy.
- Yaxin Li
- , Hao Shen
- & Junyu Xiao
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Structures and mechanisms of tRNA methylation by METTL1–WDR4
Using cryo-electron microscopy, structural and mechanistic insights into how the METTL1–WDR4 complex catalyses methylation of tRNAs are shown.
- Victor M. Ruiz-Arroyo
- , Rishi Raj
- & Yunsun Nam
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Antiviral signalling by a cyclic nucleotide activated CRISPR protease
A CalpL–CalpT–CalpS cascade mediated by cyclic oligoadenylates is identified as a mechanism to detect viral RNA and activate subsequent antivirus responses in microorganisms.
- Christophe Rouillon
- , Niels Schneberger
- & Gregor Hagelueken
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Plant receptor-like protein activation by a microbial glycoside hydrolase
A structural analysis focusing on plant immunity reveals how LRR-containing receptor-like proteins recognize pathogenic ligands and consequently become activated, with the data suggesting that these proteins target pathogens through two different mechanisms.
- Yue Sun
- , Yan Wang
- & Jijie Chai
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Article
| Open AccessR-loop formation and conformational activation mechanisms of Cas9
Cryo-electron microscopy structures of Streptococcus pyogenes Cas9 in multiple DNA-bound states provide insights on the mechanism of Cas9 activation by target DNA.
- Martin Pacesa
- , Luuk Loeff
- & Martin Jinek
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Article
| Open AccessDiscovery, structure and mechanism of a tetraether lipid synthase
In Methanocaldococcus jannaschii, a radical S-adenosylmethionine enzyme catalyses the formation of the biphytanyl chain.
- Cody T. Lloyd
- , David F. Iwig
- & Squire J. Booker
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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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Molecular basis for the initiation of DNA primer synthesis
The molecular determinants for primer synthesis are identified within the catalytic domain of primase-polymerase enzymes, elucidating the mechanisms underlying initiation of primer synthesis.
- Arthur W. H. Li
- , Katerina Zabrady
- & Aidan J. Doherty
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Article
| Open AccessPhage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity
A study using a biochemical screen of 57 phages in two bacterial species identifies and characterizes proteins enabling phages to evade CBASS and Pycsar immune systems, and describes the mechanisms involved.
- Samuel J. Hobbs
- , Tanita Wein
- & Philip J. Kranzusch
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Discovery of a Ni2+-dependent guanidine hydrolase in bacteria
A bacterial enzyme is characterized and demonstrated to have Ni2+-dependent activity and high specificity for free guanidine enabling the bacteria to use guanidine as the sole nitrogen source for growth.
- D. Funck
- , M. Sinn
- & J. S. Hartig
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Article
| Open AccessVisualizing protein breathing motions associated with aromatic ring flipping
Nuclear magnetic resonance spectroscopy and X-ray crystallography capture how aromatic side chains can flip within the core of a protein via the generation of a local void volume.
- Laura Mariño Pérez
- , Francesco S. Ielasi
- & Malene Ringkjøbing Jensen
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Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias
Extracellular glioblastoma-associated mutations reduce the ability of the epidermal growth factor receptor to distinguish between its ligands.
- Chun Hu
- , Carlos A. Leche II
- & Mark A. Lemmon
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Structure of a B12-dependent radical SAM enzyme in carbapenem biosynthesis
X-ray crystal structures of TokK, a cobalamin- or B12-dependent radical SAM methylase, provide insight into how these enzymes use sequential radical-mediated methylations to assemble the C6 side chain of carbapenem antibiotics.
- Hayley L. Knox
- , Erica K. Sinner
- & Squire J. Booker
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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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Structures of the σ2 receptor enable docking for bioactive ligand discovery
Crystal structures of the σ2 receptor are determined and used to perform a docking screen of nearly 500 million molecules, identifying σ2-selective ligands and providing insight into the role of σ2 in neuropathic pain.
- Assaf Alon
- , Jiankun Lyu
- & Andrew C. Kruse
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Article
| Open AccessAccuracy mechanism of eukaryotic ribosome translocation
Structural analysis of the Saccharomyces cerevisiae 80S ribosome trapped in an intermediate translocation state shows stabilization of codon–anticodon interactions by eukaryote-specific elements of the 80S ribosome, eEF2 and tRNA and demonstrates a major role for eEF2 in maintaining the directionality of translocation.
- Muminjon Djumagulov
- , Natalia Demeshkina
- & Gulnara Yusupova
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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 basis for ligand reception by anaplastic lymphoma kinase
Analysis of crystal structures of anaplastic lymphoma kinase elucidate the mechanism by which ligand binding and the glycine-rich domain regulate its activity.
- Tongqing Li
- , Steven E. Stayrook
- & Daryl E. Klein
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Host immunomodulatory lipids created by symbionts from dietary amino acids
The symbiotic gut bacterium Bacteroides fragilis produces unique α-galactosylceramides from host dietary branched-chain amino acids, which are presented as CD1d ligands and immunomodulate natural killer T cells.
- Sungwhan F. Oh
- , T. Praveena
- & Dennis L. Kasper
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A synthetic antibiotic class overcoming bacterial multidrug resistance
Structure-guided design and component-based synthesis are used to produce iboxamycin, a novel ribosome-binding antibiotic with potent activity against Gram-positive and Gram-negative bacteria.
- Matthew J. Mitcheltree
- , Amarnath Pisipati
- & Andrew G. Myers
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Structural basis of cytokine-mediated activation of ALK family receptors
Structural studies of the complex of anaplastic lymphoma kinase and leukocyte tyrosine kinase and their activating cytokines identify unique architectural features of the complex, and provide a novel mechanistic paradigm among receptor tyrosine kinases.
- Steven De Munck
- , Mathias Provost
- & Savvas N. Savvides
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Article |
A single sulfatase is required to access colonic mucin by a gut bacterium
A single sulfatase produced by a bacterium found in the human colon is essential for degradation of sulfated O-glycans in secreted mucus.
- Ana S. Luis
- , Chunsheng Jin
- & Eric C. Martens
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Structural insights into hepatitis C virus receptor binding and entry
Crystal structures of the hepatitis C virus (HCV) glycoprotein E2 in complex with CD81 reveal the conformational changes that occur in E2 after binding of CD81 and the effects of pH on binding affinity.
- Ashish Kumar
- , Reafa A. Hossain
- & Joseph Marcotrigiano
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Structural basis for tRNA methylthiolation by the radical SAM enzyme MiaB
Crystal structures reveal the catalytic mechanism through which the radical S-adenosylmethionine enzyme MiaB adds a methylthio group onto tRNA.
- Olga A. Esakova
- , Tyler L. Grove
- & Squire J. Booker
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Article |
Molecular basis for DarT ADP-ribosylation of a DNA base
Structural and mechanistic data of the ADP-ribosyltransferase DarT demonstrate the role of ADP-ribosylation of DNA by this enzyme in generating toxicity and regulating cellular signalling processes in bacteria.
- Marion Schuller
- , Rachel E. Butler
- & Ivan Ahel
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Article |
Broad sarbecovirus neutralization by a human monoclonal antibody
The human monoclonal antibody S2X259 cross-reacts with spike proteins from all clades of sarbecovirus, and provides prophylactic and therapeutic protection in vivo against parental SARS-CoV-2 and emerging variants of concern.
- M. Alejandra Tortorici
- , Nadine Czudnochowski
- & Matteo Samuele Pizzuto
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Article |
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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The antibiotic darobactin mimics a β-strand to inhibit outer membrane insertase
Structural studies resolve how the antibiotic darobactin inhibits the bacterial BAM insertase.
- Hundeep Kaur
- , Roman P. Jakob
- & Sebastian Hiller
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Article |
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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The Card1 nuclease provides defence during type III CRISPR immunity
Structural analyses of the type III CRISPR accessory protein Card1, which induces dormancy in infected hosts to provide immunity against phage infection, reveal the mechanisms by which it cleaves single-stranded RNA and DNA.
- Jakob T. Rostøl
- , Wei Xie
- & Luciano A. Marraffini
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Article |
Ultrafast structural changes within a photosynthetic reaction centre
Time-resolved serial femtosecond crystallography is used to reveal the structural changes that stabilize the charge-separation steps of electron-transfer reactions in the photosynthetic reaction centre of Blastochloris viridis on a timescale of picoseconds.
- Robert Dods
- , Petra Båth
- & Richard Neutze
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Article |
Structure and function of virion RNA polymerase of a crAss-like phage
The RNA polymerase from the crAss-like bacteriophage phi14:2, which is translocated into the host cell with phage DNA and transcribes early phage genes, is structurally most similar to eukaryotic RNA interference polymerases, suggesting that the latter have a phage origin.
- Arina V. Drobysheva
- , Sofia A. Panafidina
- & Maria L. Sokolova
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Structural basis for the action of the drug trametinib at KSR-bound MEK
Crystal structures of the MEK kinase bound to the scaffold protein KSR and various MEK inhibitors, including the anti-cancer drug trametinib, reveal the molecular and functional mechanisms behind MEK inhibition.
- Zaigham M. Khan
- , Alexander M. Real
- & Arvin C. Dar
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Article |
STING cyclic dinucleotide sensing originated in bacteria
Structures of prokaryotic homologues of STING permit the reconstruction of the evolutionary trajectory of its incorporation into metazoan innate immunity, and reveal a role for the conserved cGAS–STING pathway in prokaryotic defence against bacteriophages.
- Benjamin R. Morehouse
- , Apurva A. Govande
- & Philip J. Kranzusch
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Article |
Structural basis of salicylic acid perception by Arabidopsis NPR proteins
Structural determination of the salicylic-acid-binding core of Arabidopsis NPR4 sheds light on the mechanisms through which this plant hormone interacts with its receptors, providing insights that are of potential use in engineering enhanced immunity.
- Wei Wang
- , John Withers
- & Ning Zheng
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Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity
Biochemical, structural and functional studies on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like protease PLpro reveal that it regulates host antiviral responses by preferentially cleaving the ubiquitin-like interferon-stimulated gene 15 protein (ISG15) and identify this protease as a potential therapeutic target for coronavirus disease 2019 (COVID-19).
- Donghyuk Shin
- , Rukmini Mukherjee
- & Ivan Dikic
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Structures of fungal and plant acetohydroxyacid synthases
Structures of the acetohydroxyacid synthase complexes of Saccharomyces cerevisiae and Arabidopsis thaliana provide insights into the biosynthesis of and feedback inhibition by branched-chain amino acids.
- Thierry Lonhienne
- , Yu Shang Low
- & Luke W. Guddat
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Clinical targeting of HIV capsid protein with a long-acting small molecule
The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection.
- John O. Link
- , Martin S. Rhee
- & Tomas Cihlar