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| Open AccessEpigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis
Radiotherapy can induce fibrosis in cancer patients, limiting its use in clinical settings. Here, the authors identify a differentially methylated enhancer of the lipid kinase DGKA in fibroblasts from breast cancer patients developing fibrosis after radiotherapy and they show that DGKA inhibition affects lipid homeostasis and reduces pro-fibrotic fibroblast activation.
- Christoph Weigel
- , Marlon R. Veldwijk
- & Odilia Popanda
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Article
| Open AccessStructural basis for selective recognition of acyl chains by the membrane-associated acyltransferase PatA
PatA is a membrane-associated acyltransferase that is essential for the biosynthesis of mycobacterial glycolipids. Here, Albesa-Jovéet al. describe structures of PatA from Mycobacterium smegmatisin complex with acyl donors and show that catalysis occurs by an unusual charge-relay mechanism.
- David Albesa-Jové
- , Zuzana Svetlíková
- & Marcelo E. Guerin
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Article
| Open AccessThe unconventional myosin CRINKLED and its mammalian orthologue MYO7A regulate caspases in their signalling roles
In addition to their role in apoptosis, caspases are also involved in mediating non-apoptotic events. Here the authors show that the Drosophilamyosin family member CRINKLED and its mammalian counterpart act as substrate adaptor that facilitate caspase-mediated cleavage and localised kinase activity.
- Mariam H. Orme
- , Gianmaria Liccardi
- & Pascal Meier
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Article
| Open AccessUnmasking the ancestral activity of integron integrases reveals a smooth evolutionary transition during functional innovation
The integron integrases have evolved to perform recombination of single and double stranded DNA. Here the authors show that the ancestral pathway is still functional at double stranded sites, revealing the evolution towards the modern resolution pathway.
- Jose Antonio Escudero
- , Celine Loot
- & Didier Mazel
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Article
| Open AccessManipulation of prenylation reactions by structure-based engineering of bacterial indolactam prenyltransferases
Regioselective prenylation of small aromatic natural molecules is crucial for their biological activity. Here, the authors present the biochemical and structural characterisation of two prenyltransferases and a structure-based engineering strategy to modulate their substrate specificity.
- Takahiro Mori
- , Lihan Zhang
- & Ikuro Abe
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Article
| Open AccessAMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B
The diabetes drug Metformin decreases hepatic glucose production and activates AMP-activated protein kinase (AMPK). Here the authors provide evidence that AMPK activation antagonizes glucagon signalling by activating PDE4B, lowering cAMP levels and decreasing PKA activation.
- M. Johanns
- , Y.-C. Lai
- & M H Rider
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Article
| Open AccessItk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4
The Tec family tyrosine kinase, Itk, is a component of the T-cell receptor essential for optimal Th2 responses in vivo. Here the authors show in human cells and mouse models that Itk is also needed for the production of IL-9, an important contributor to allergic asthma.
- Julio Gomez-Rodriguez
- , Françoise Meylan
- & Pamela L. Schwartzberg
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Article
| Open AccessMT1-MMP sheds LYVE-1 on lymphatic endothelial cells and suppresses VEGF-C production to inhibit lymphangiogenesis
Blocking lymphangiogenesis holds great therapeutic potential, however, only few inhibitors are known. Here the authors show that membrane type 1-matrix metalloproteinase suppresses lymphangiogenesis by curbing both LYVE-1-mediated proliferation of lymphatic endothelial cells and production of lymphangiogenic factors by macrophages.
- Hoi Leong Xavier Wong
- , Guoxiang Jin
- & Zhongjun Zhou
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Article
| Open AccessImpact of ribonucleotide incorporation by DNA polymerases β and λ on oxidative base excision repair
Oxidative stress is a common source of DNA damage and is repaired by the base excision repair machinery, including polymerase beta. Here the authors find that polymerase beta, and to a lesser extent lambda, can mistakenly incorporate ribonucleotides during synthesis.
- Emmanuele Crespan
- , Antonia Furrer
- & Giovanni Maga
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Article
| Open AccessThe Bub1–Plk1 kinase complex promotes spindle checkpoint signalling through Cdc20 phosphorylation
The mitotic checkpoint complex (MCC) inhibits the anaphase-promoting complex (APC/C) bound to Cdc20 in response to spindle defects. Here, the authors show that Bub1-Plk1-mediated phosphorylation of Cdc20 constitutes a parallel, non-redundant APC/C-inhibitory mechanism in addition to MCC activity.
- Luying Jia
- , Bing Li
- & Hongtao Yu
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Article
| Open AccessThe RNA helicase DHX34 functions as a scaffold for SMG1-mediated UPF1 phosphorylation
UPF1 is a central Nonsense-mediated mRNA decay—(NMD), a mechanism to degrade mRNAs containing premature translation termination codons-factor—whose phosphorylation is key to triggering NMD. Here the authors show that the DHX34 helicase acts as a scaffold in promoting UPF1 phosphorylation by SMG1 to promotes NMD.
- Roberto Melero
- , Nele Hug
- & Oscar Llorca
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Article
| Open AccessPKR is not obligatory for high-fat diet-induced obesity and its associated metabolic and inflammatory complications
Protein kinase R (PKR) has been suggested to act as a mediator of ER stress and inflammation in obesity. Here, Lancaster et al. find that genetic loss of PKR does not alter the development of obesity, and suggest that the use of littermate controls may explain differences in mouse knockout phenotypes.
- G. I. Lancaster
- , H. L. Kammoun
- & M. A. Febbraio
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Article
| Open AccessMolecular sled is an eleven-amino acid vehicle facilitating biochemical interactions via sliding components along DNA
Extremely compact environments can inhibit protein interactions by preventing 3-dimensional diffusion. Here the authors show that an 11-amino acid long peptide can function as a ‘molecular sled’, able to transport cargo linearly along DNA to enable interactions.
- Walter F. Mangel
- , William J. McGrath
- & Paul C. Blainey
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Article
| Open AccessMDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification
Vascular calcification (VC) increases morbidity and mortality in cardiovascular and metabolic diseases. Here, Kwon et al.show that calcification stimuli induce MDM2- mediated ubiquitination and proteasomal degradation of HDAC1, suggesting a possible therapeutic strategy for treatment of VC patients.
- Duk-Hwa Kwon
- , Gwang Hyeon Eom
- & Hyun Kook
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Article
| Open AccessNuclear AURKA acquires kinase-independent transactivating function to enhance breast cancer stem cell phenotype
Aurora kinase A is a mitotic kinase that facilitates G2/M events. Here the authors show that in breast cancer cells Aurora kinase A has a kinase-independent function in the nucleus by activating the MYC promoter in cooperation with hnRNP K, enhancing the breast cancer stem cell phenotype.
- Feimeng Zheng
- , Caifeng Yue
- & Quentin Liu
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Article
| Open AccessThe Atg1–kinase complex tethers Atg9-vesicles to initiate autophagy
Autophagosome biogenesis is initiated by recruitment of Atg9-vesicles to the phagophore assembly site. Here Rao et al. use a reconstituted in vitrosystem to describe the mechanism by which activation of the Atg1-kinase complex from its constituent parts recruits and tethers Atg9-vesicles.
- Yijian Rao
- , Marco G. Perna
- & Thomas Wollert
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Article
| Open AccessCrystal structure of E. coli lipoprotein diacylglyceryl transferase
Bacterial lipoproteins have important biological functions, and the lipoprotien biogenesis enzyme Lgt is essential in most gram-negative bacteria. Here, the authors use structural and biochemical techniques to shed light on the function of Lgt in post-translational transacylation modification.
- Guotao Mao
- , Yan Zhao
- & Xuejun C. Zhang
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Article
| Open AccessStructure of the polyisoprenyl-phosphate glycosyltransferase GtrB and insights into the mechanism of catalysis
Polyisoprenyl-glycosyltransferases (PI-GTs) catalyse the addition of sugar to lipid carriers, which is the first step in the production of sugar donors for glycosylation. Here Ardiccioni et al.present the structure of a bacterial PI-GT and propose a mechanistic basis for sugar transfer.
- Chiara Ardiccioni
- , Oliver B. Clarke
- & Filippo Mancia
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| Open AccessTernary structure reveals mechanism of a membrane diacylglycerol kinase
Diacylglycerol kinase is a small bacterial membrane-bound trimer that catalyses diacylglycerol conversion to phosphatidic acid. Here, the authors solve the crystal structure of the kinase bound to a lipid substrate and an ATP analogue, and show that the active site arose through convergent evolution.
- Dianfan Li
- , Phillip J. Stansfeld
- & Martin Caffrey
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Article
| Open AccessT7 replisome directly overcomes DNA damage
Genomic instability can result from stalled or collapsed replication fork at sites of unrepaired DNA lesions. Here the authors uncover a new lesion bypass pathway for the T7 replisome, where leading strand template lesions can be overcome through interaction between the replisome's helicase and polymerase components.
- Bo Sun
- , Manjula Pandey
- & Michelle D. Wang
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Article
| Open AccessTank binding kinase 1 is a centrosome-associated kinase necessary for microtubule dynamics and mitosis
TANK binding kinase 1 (TBK1) is a non-canonical IκB kinase that regulates immunity via NF-κB. Here Pillai et al. show that TBK1 localizes to centrosomes during mitosis, and regulates microtubule dynamics and spindle formation by phosphorylating the centrosomal protein CEP170 and the mitotic apparatus protein NuMa.
- Smitha Pillai
- , Jonathan Nguyen
- & Srikumar Chellappan
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Article
| Open AccessCellobiohydrolase 1 from Trichoderma reesei degrades cellulose in single cellobiose steps
Cellobiohydrolases are promising tools in biofuel production by hydrolysing cellulose into cellobiose. Here the authors use optical tweezers to show that Cellobiohydrolase 1 fromTricodermia reeseifunctions processively against moderate load, and likely uses multiple energy sources to fuel each step along the cellulose fibre.
- Sonia K. Brady
- , Sarangapani Sreelatha
- & Matthew J Lang
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Article
| Open AccessStructural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin
Type IIA topoisomerases (topo2As) create transient double-strand DNA breaks. Here, the authors report structures showing how QPT-1 binds in the DNA/topo2A complex at the same site as the fluoroquinolone moxifloxacin, and discuss the potential for developing new classes of antibiotics.
- Pan F. Chan
- , Velupillai Srikannathasan
- & Michael N. Gwynn
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Article
| Open AccessUltrahigh-throughput discovery of promiscuous enzymes by picodroplet functional metagenomics
Environmental DNA from unculturable microorganisms contains genes with useful functions that remain difficult to identify and isolate. Here Colin, Kintses et al.demonstrate the screening of millions of samples in pL volumes to directly identify new enzymatic activities and complements sequence-based approaches.
- Pierre-Yves Colin
- , Balint Kintses
- & Florian Hollfelder
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Article
| Open AccessStructural insight into the mechanism of synergistic autoinhibition of SAD kinases
The SAD kinases contain a UBA domain that binds to the kinase domain and has a role in autoinhibition and allosteric activation of the AMPK homoenzyme. Here, the authors identify an autoinhibitory sequence in SAD and show that the UBA domain synergistically functions as an autoinhibitory domain.
- Jing-Xiang Wu
- , Yun-Sheng Cheng
- & Jia-Wei Wu
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Article
| Open AccessA tyrosine–tryptophan dyad and radical-based charge transfer in a ribonucleotide reductase-inspired maquette
Tyrosine-tryptophan dyads are known to mediate electron transfer reactions in a range of different proteins. Here, the authors study a beta hairpin peptide, probing the tyrosine-tryptophan interaction and showing no hydrogen bonding but rather charge transfer between the tyrosyl radical and tryptophan'.
- Cynthia V. Pagba
- , Tyler G. McCaslin
- & Bridgette A. Barry
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Article
| Open AccessA molecular ruler regulates cytoskeletal remodelling by the Rho kinases
Rho kinases regulate the actin cytoskeleton by controlling stress fibre formation. Truebestein et al.show that the length of its coiled-coil determines ROCK2 function, and propose that the coiled coil acts as a spacer, targeting kinase activity to a discrete distance from the membrane.
- Linda Truebestein
- , Daniel J. Elsner
- & Thomas A. Leonard
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Article
| Open AccessAlternative splicing of Drosophila Nmnat functions as a switch to enhance neuroprotection under stress
Nicotinamide mononucleotide adenylyltransferase (NMNAT) acts in the NAD biosynthesis pathway and has neuroprotective activity. Ruan et al. show that the neuroprotective activity of NMNAT is restricted to a splice variant of the enzyme, and that this variant is preferentially spliced in response to stress.
- Kai Ruan
- , Yi Zhu
- & R. Grace Zhai
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Article
| Open AccessAn in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1
PAK4 is a metazoan-specific kinase, which acts downstream of the cell polarity regulator Cdc42. Here, Baskaran et al.determine the structure of PAK4 bound to the endogenous inhibitor Inka1 from crystals that form spontaneously in mammalian cells overexpressing both proteins.
- Yohendran Baskaran
- , Khay C. Ang
- & Robert C. Robinson
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Article
| Open AccessWnt/β-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance
The high expression of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) often confers resistance to chemotherapy in several cancers. In this study, the authors propose the inhibition of the Wnt signalling pathway as an alternative strategy to modulate MGMT expression and sensitize tumours to chemotherapy.
- Malin Wickström
- , Cecilia Dyberg
- & John Inge Johnsen
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Article
| Open AccessStructure and substrate selectivity of the 750-kDa α6β6 holoenzyme of geranyl-CoA carboxylase
The structures of the biotin-dependent carboxylases have revealed details of their function. Here, the authors describe the first structure of Pseudomonasgeranyl-CoA carboxylase, and compare it with the previously characterised homologous 3-methylcrotonyl-CoA carboxylase.
- Ashley R. Jurado
- , Christine S. Huang
- & Liang Tong
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Article
| Open AccessComplementation between polymerase- and exonuclease-deficient mitochondrial DNA polymerase mutants in genomically engineered flies
A key source of mitochondrial DNA mutations is errors introduced during genome replication. Here the authors create Drosophiliastrains with separated elongation and proofreading capabilities to explore the dynamism of mitochondrial DNA replication.
- Ana Bratic
- , Timo E. S. Kauppila
- & Nils-Göran Larsson
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Article
| Open AccessTargeting of SUMO substrates to a Cdc48–Ufd1–Npl4 segregase and STUbL pathway in fission yeast
The small ubiquitin-like modifier SUMO can be conjugated to hundreds of protein species to affect their stability or activity. Here the authors use a quantitative proteomics approach to identify sumoylated proteins modified by the STUbL and Ufd1 pathways in fission yeast.
- Julie Bonne Køhler
- , Triin Tammsalu
- & Geneviève Thon
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Article
| Open AccessLoss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism
Evidence suggests that the TCA cycle enzyme complex succinate dehydrogenase (SDH) may be dispensable for cell proliferation in some cancer cells. Here the authors show that SDH deficient cells become dependent on the mitochondrial enzyme pyruvate carboxylase for aspartate production and proliferation.
- Charlotte Lussey-Lepoutre
- , Kate E. R. Hollinshead
- & Daniel A. Tennant
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Article
| Open AccessMechanistic basis of Nek7 activation through Nek9 binding and induced dimerization
NEK7, a kinase involved in mitosis, is regulated by the kinase NEK9. Here the authors identify the region in NEK9 that binds NEK7 and find that the mechanism of regulation involves dimerization coupled to structural changes in the active site.
- Tamanna Haq
- , Mark W. Richards
- & Richard Bayliss
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Article
| Open AccessDegradation of the ABA co-receptor ABI1 by PUB12/13 U-box E3 ligases
Signaling by the plant hormone abscisic acid (ABA) is regulated by the ABI1 protein phosphatase. Here Kong et al.propose that ABA signaling is fine-tuned by ubiquitination of ABI1 which promotes ABI degradation in response to ABA.
- Lingyao Kong
- , Jinkui Cheng
- & Zhizhong Gong
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Article
| Open AccessFR171456 is a specific inhibitor of mammalian NSDHL and yeast Erg26p
FR171456 is a bioactive chemical produced by some microorganisms. Here, the authors identify the enzyme NSDHL of the sterol synthesis pathway as the molecular target of FR171456, rendering it the first compound to specifically target this class of enzyme in yeast and mammalian cells.
- Stephen B. Helliwell
- , Shantanu Karkare
- & Christian N. Parker
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Article
| Open AccessCatalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice
Inhibiting insulin-degrading enzyme (IDE) has been proposed as a potential therapeutic strategy for the treatment of patients with diabetes. Here, the authors develop a novel IDE inhibitor but find that, surprisingly, IDE inhibition has negative effects on glucose tolerance in mice.
- Rebecca Deprez-Poulain
- , Nathalie Hennuyer
- & Benoit Deprez
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Article
| Open AccessProteomics of yeast telomerase identified Cdc48-Npl4-Ufd1 and Ufd4 as regulators of Est1 and telomere length
Regulating telomere length and telomerase activity are critical biological processes implicated in ageing and cancer. Here the authors use mass spectrometry to identify the Cdc48-Npl4-Ufd1 complex, which targets proteins for degradation, as a novel regulator of the yeast telomerase Est1.
- Kah-Wai Lin
- , Karin R. McDonald
- & Virginia A. Zakian
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Article
| Open AccessResolution of structure of PIP5K1A reveals molecular mechanism for its regulation by dimerization and dishevelled
Type I phosphatidylinositol phosphate kinase is an important component of many cellular pathways, including Wnt signalling. Here the authors report the crystal structure of the zebrafish protein along with in vitroassays that help to elucidate the regulation and function of this kinase.
- Jian Hu
- , Qianying Yuan
- & Dianqing Wu
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Article
| Open AccessIntegrin-linked kinase regulates the niche of quiescent epidermal stem cells
Integrin-linked kinase (ILK) is known to modulate the extracellular matrix and hair follicle morphogenesis. Here, Morgner et al.show that lack of ILK causes an aberrant ratio of basement membrane laminins, activating stem cells and predisposing skin to carcinogenesis.
- Jessica Morgner
- , Sushmita Ghatak
- & Sara A. Wickström
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Article
| Open AccessKinase-independent role for CRAF-driving tumour radioresistance via CHK2
Tumors hijack cellular pathways to evade the effects of cancer therapy. Here, Advaniet al. show that DNA damage-induced phosphorylation of CRAF Serine 338 triggers DNA repair by recruiting CHK2, highlighting a role for CRAF independent from its canonical function as a kinase.
- Sunil J. Advani
- , Maria Fernanda Camargo
- & David A. Cheresh
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Article
| Open AccessActivity-regulated trafficking of the palmitoyl-acyl transferase DHHC5
Synaptic plasticity is mediated by the dynamic localization of proteins at synapses, which is partly controlled via palmitoylation of synaptic proteins. Here, the authors show how neuronal activity regulates the palmitoylation reaction through the translocation of the palmitoyl-acyl transferase DHHC5.
- G. Stefano Brigidi
- , Brendan Santyr
- & Shernaz X. Bamji
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Article
| Open AccessRefining the pathway of carbide insertion into the nitrogenase M-cluster
Carbide insertion plays a pivotal role in the biosynthesis of M-cluster, the cofactor of nitrogenase. Here the authors further define the pathway for interstitial carbide atom insertion, showing that the SAM-derived methyl group is transferred to a FeS precursor sulfur before hydrogen abstraction via an SN2-type reaction.
- Jared A. Wiig
- , Yilin Hu
- & Markus W. Ribbe
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Article
| Open AccessHydride bridge in [NiFe]-hydrogenase observed by nuclear resonance vibrational spectroscopy
Understanding the catalytic mechanism of redox-active hydrogenases is a key to efficient hydrogen production and consumption. Here, the authors use nuclear resonance vibrational spectroscopy to study [NiFe]-hydrogenase, and observe a bridging hydride structure in an EPR silent intermediate.
- Hideaki Ogata
- , Tobias Krämer
- & Stephen P. Cramer
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Article |
Oestrogen sulfotransferase ablation sensitizes mice to sepsis
Sepsis, a systemic inflammatory response to bacterial infection, can lead to organ failure and death. Here, Chai et al.investigate the mechanisms behind the septic response and identify the role of oestrogen sulfotransferase in this process in mice.
- Xiaojuan Chai
- , Yan Guo
- & Wen Xie
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Article
| Open AccessCrystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2
Dysfunctional redox regulation in cancer can damage dNTPs so inhibiting dNTP pool sanitizing enzymes, such as MTH1, is a potential cancer treatment. Here, Carter et al.characterize MTH2 (NUDT15) and show that it is not a dNTP sanitizer, and so is unlikely to influence the efficacy of MTH1 inhibitors.
- Megan Carter
- , Ann-Sofie Jemth
- & Pål Stenmark
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Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs
Sensory neurons that mediate histamine-independent itch express Mas-related G protein coupled receptors (Mrgprs). Here, Reddy et al.show that the cysteine protease cathepsin S cleaves and activates MrgpcrC11 without the generation of a tethered ligand, in contrast to other protease activated receptors.
- Vemuri B. Reddy
- , Shuohao Sun
- & Ethan A. Lerner
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Article
| Open AccessStructural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase
Receptor tyrosine kinases are key mediators of cell proliferation that have been implicated in several disease states for which they represent promising drug targets. Here the authors determine the thermodynamic basis for the low propensity of FGFR1 to access the DFG-Phe-out conformation required to bind type-II inhibitors.
- Tobias Klein
- , Navratna Vajpai
- & Alexander L. Breeze