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| Open AccessStructural and functional analysis of mRNA export regulation by the nuclear pore complex
The export of mRNA to the cytosol depends on the nuclear pore complex (NPC) and the activation of the helicase DDX19, but their interplay in humans remains poorly understood. Here, the authors present a structural and functional analysis of DDX19 activation, revealing how the human NPC regulates mRNA export.
- Daniel H. Lin
- , Ana R. Correia
- & André Hoelz
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Article
| Open AccessHydrophobic pore gates regulate ion permeation in polycystic kidney disease 2 and 2L1 channels
Mutations in the cation channel PKD2 cause human autosomal dominant polycystic kidney disease but its channel function and gating mechanism are poorly understood. Here authors study PKD2 using electrophysiology and cryo-EM, which identifies hydrophobic gates and proposes a gating mechanism for PKD2.
- Wang Zheng
- , Xiaoyong Yang
- & Xing-Zhen Chen
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Article
| Open AccessLipid vesicles chaperone an encapsulated RNA aptamer
So far little is known about how encapsulation affects the activity and folding of RNA, which is of interest for understanding the origin of cellular life. Here the authors show that encapsulation of functional RNA in vesicles increases RNA activity and improves RNA folding through a biophysical confinement effect.
- Ranajay Saha
- , Samuel Verbanic
- & Irene A. Chen
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Article
| Open AccessSpatially confined lignin nanospheres for biocatalytic ester synthesis in aqueous media
Development of biocatalysts that mimic compartmentalized reactions in cells has been cumbersome due to the lack of low-cost materials and associated technologies. Here the authors show that cationic lignin nanospheres function as activating anchors for hydrolases, and enable aqueous ester synthesis by forming spatially confined biocatalysts.
- Mika Henrikki Sipponen
- , Muhammad Farooq
- & Monika Österberg
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Article
| Open AccessOxidized phospholipids regulate amino acid metabolism through MTHFD2 to facilitate nucleotide release in endothelial cells
During atherosclerosis, endothelial cells release purines in response to oxidized phospholipids. Here, Hitzel et al. show that oxidized phospholipids activate an MTHFD2-regulated gene network in endothelial cells which reprograms amino acid metabolism towards production of purines and thus compensates for their loss.
- Juliane Hitzel
- , Eunjee Lee
- & Ralf P. Brandes
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Article
| Open AccessStructural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition
The human enzyme MTHFR links the folate and methionine cycles, which are essential for the biosynthesis of nucleotides and proteins. Here, the authors present the crystal structure and biochemical analysis of human MTHFR, providing molecular insights into its function and regulation in higher eukaryotes.
- D. Sean Froese
- , Jolanta Kopec
- & Wyatt W. Yue
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Article
| Open AccessCellular stress alters 3′UTR landscape through alternative polyadenylation and isoform-specific degradation
The function and consequences of alternative polyadenylation (APA) in stressed cells are largely unclear. Here, the authors show that stress-induced mRNA degradation depends on 3′UTR length and that APA-mediated 3′UTR shortening is an adaptive stress response mechanism for selective transcript stabilization.
- Dinghai Zheng
- , Ruijia Wang
- & Bin Tian
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Article
| Open AccessSKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity
Regulation of Yes-associated protein (YAP) through the Hippo pathway is well established, but its Hippo-independent regulation remains to be elucidated. Here, the authors show that non-proteolytic ubiquitination presents another means of YAP regulation, promoting its nuclear localization and activity.
- Fan Yao
- , Zhicheng Zhou
- & Li Ma
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Article
| Open AccessAn anionic phthalocyanine decreases NRAS expression by breaking down its RNA G-quadruplex
Hyperactivity of the gene NRAS contributes to the proliferation and metastatic nature of many types of cancer cells. Here, the authors show that NRAS can be controlled by an anionic phthalocyanine coordinating Zn2+ in combination with photo-irradiation.
- Keiko Kawauchi
- , Wataru Sugimoto
- & Daisuke Miyoshi
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Article
| Open AccessMolecular principles underlying dual RNA specificity in the Drosophila SNF protein
It remains poorly understood how a single RNA-binding protein recognizes diverse RNA targets. Here the authors use an integrative approach to study the binding of spliceosomal SNF protein to U1 and U2 small nuclear RNAs in the presence or absence of auxiliary protein U2A’ and show how SNF’s conformational dynamics are tuned to recognize different stem-loop structures.
- Gert Weber
- , Gregory T. DeKoster
- & Markus C. Wahl
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Article
| Open AccessModular ssDNA binding and inhibition of telomerase activity by designer PPR proteins
Pentatricopeptide repeat proteins bind single-stranded RNA and have been used to study ssRNA biology. Here the authors co-opt these proteins to target ssDNA and demonstrate specific binding of telomere sequences, the structural basis for ssDNA wrapping, and use them as potent telomerase inhibitors.
- Henrik Spåhr
- , Tiongsun Chia
- & Oliver Rackham
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Article
| Open AccessMultiple communication mechanisms between sensor kinases are crucial for virulence in Pseudomonas aeruginosa
Bacteria respond to stresses using two-component systems consisting of sensor kinases (SKs) and response regulators. Here, Francis et al. reveal three specific interaction mechanisms between a pair of SKs that are important for regulation of virulence in the pathogen Pseudomonas aeruginosa.
- Vanessa I. Francis
- , Elaine M. Waters
- & Steven L. Porter
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Article
| Open AccessHuR regulates telomerase activity through TERC methylation
Mutations in the RNA component TERC can cause telomerase dysfunction but the underlying mechanisms are largely unknown. Here, the authors show that RNA-binding protein HuR regulates telomerase function by enhancing the methylation of TERC, which is impaired by several disease-relevant TERC mutations.
- Hao Tang
- , Hu Wang
- & Wengong Wang
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Article
| Open AccessAlternative assembly of respiratory complex II connects energy stress to metabolic checkpoints
Mitochondrial complex II is normally composed of four subunits. Here the authors show that bioenergetic stress conditions give rise to a partially assembled variant of complex II, which shifts the anabolic pathways to less energy demanding processes.
- Ayenachew Bezawork-Geleta
- , He Wen
- & Jiri Neuzil
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Article
| Open AccessVms1p is a release factor for the ribosome-associated quality control complex
The ribosome-associated quality control complex (RQC) functions to disassemble stalled ribosomes. Here the authors find that the tRNA hydrolase Vms1 is involved in the release of nascent peptide from stalled ribosomes.
- Olga Zurita Rendón
- , Eric K. Fredrickson
- & Jared Rutter
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Article
| Open AccessArtificial strain of human prions created in vitro
Synthetic prions have previously been generated from recombinant rodent PrP. Here the authors generate synthetic human prions, by seeding human PrP with CJD prions, and characterize its infectivity in mice.
- Chae Kim
- , Xiangzhu Xiao
- & Jiri G. Safar
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Correspondence
| Open AccessOn the role of STAT1 and STAT6 ADP-ribosylation in the regulation of macrophage activation
- Andreas Begitt
- , James Cavey
- & Uwe Vinkemeier
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Article
| Open AccessDynamic structural states of ClpB involved in its disaggregation function
The bacterial protein disaggregation machine ClpB uses ATP to generate mechanical force to unfold and thread its protein substrates. Here authors visualize the ClpB ring using high-speed atomic force microscopy and capture conformational changes of the hexameric ring during the ATPase reaction.
- Takayuki Uchihashi
- , Yo-hei Watanabe
- & Toshio Ando
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Article
| Open AccessCellular conditions of weakly chelated magnesium ions strongly promote RNA stability and catalysis
The concentration of divalent cations is well-known to influence molecular processes such as enzymatic activity and RNA folding. Here the authors attempt to reproduce physiological conditions for RNA folding in vitro and establish an important contribution of chelated magnesium ions in enhancing RNA function.
- Ryota Yamagami
- , Jamie L. Bingaman
- & Philip C. Bevilacqua
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Review Article
| Open AccessThe role of dynamic enzyme assemblies and substrate channelling in metabolic regulation
Temporary association of metabolic enzymes is generally assumed to facilitate substrate channelling within the complex. In this review, Lee Sweetlove and Alisdair Fernie outline the nature and functional consequence of organising enzymes into assemblies, and discuss applications within the natural world and synthetic biology.
- Lee J. Sweetlove
- & Alisdair R. Fernie
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Article
| Open AccessThe RPAP3-Cterminal domain identifies R2TP-like quaternary chaperones
R2TP is an HSP90 co-chaperone composed of an RPAP3-PIH1D1 heterodimer, which binds two essential AAA+ ATPases RUVBL1/RUVBL2. Here authors use a structural approach to study RPAP3 and find an RPAP3-like protein (SPAG1) which also forms a co-chaperone complex with PIH1D2 and RUVBL1/2 enriched in testis.
- Chloé Maurizy
- , Marc Quinternet
- & Edouard Bertrand
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Article
| Open AccessA fluorescence anisotropy assay to discover and characterize ligands targeting the maytansine site of tubulin
Microtubule-targeting agents are used successfully as anticancer therapeutics. Here authors develop a fluorescence-anisotropy-based assay to identify and characterize ligands for the maytansine site of tubulin and provide crystal structures of identified ligands in complex with tubulin.
- Grégory Menchon
- , Andrea E. Prota
- & Michel O. Steinmetz
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Article
| Open AccessStructural basis for recognition of 53BP1 tandem Tudor domain by TIRR
The p53-binding protein 1 (53BP1) regulates the choice of the DNA double-strand break repair pathway. Here the authors present the crystal structure of Tudor-interacting repair regulator (TIRR) bound to the 53BP1 tandem Tudor domain, which reveals how TIRR blocks H4K20me2 binding to 53BP1 Tudor and functionally differs from its paralog Nudt16.
- Yaxin Dai
- , Aili Zhang
- & Zheng Zhou
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Article
| Open AccessTumour-associated missense mutations in the dMi-2 ATPase alters nucleosome remodelling properties in a mutation-specific manner
ATP-dependent chromatin remodelers are often found mutated in human cancers. Here, the authors characterize the nucleosome remodelling properties of cancer-associated mutants of the Drosophila Chd4 homolog dMi-2.
- Kristina Kovač
- , Anja Sauer
- & Alexander Brehm
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Article
| Open AccessMolecular basis of dimer formation during the biosynthesis of benzofluorene-containing atypical angucyclines
Benzofluorene-containing angucyclines, bacterial natural compounds with potential use as therapeutics/antibiotics, occur as dimers. Here, the authors elucidated the dimerization mechanism which turned out to work spontaneously, without enzymatic catalysis.
- Chunshuai Huang
- , Chunfang Yang
- & Changsheng Zhang
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Article
| Open AccessRhodopsin-cyclases for photocontrol of cGMP/cAMP and 2.3 Å structure of the adenylyl cyclase domain
Cyclic AMP and cGMP orchestrate a variety of cellular responses. Here, authors characterize the cGMP producing rhodopsin-guanylyl cyclase from C. anguillulae and derived adenylyl cyclase by a biochemical and structural approach which demonstrates the usability of these cyclases for optogenetic applications.
- Ulrike Scheib
- , Matthias Broser
- & Peter Hegemann
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Article
| Open AccessCell surface flip-flop of phosphatidylserine is critical for PIEZO1-mediated myotube formation
Myotube formation by fusion of myoblasts is essential for skeletal muscle formation, but which molecules regulate this process remains elusive. Here authors identify the mechanosensitive PIEZO1 channel as a key element, whose activity is regulated by phosphatidylserine during myotube formation.
- Masaki Tsuchiya
- , Yuji Hara
- & Masato Umeda
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Article
| Open AccessTargeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
Spinal muscular atrophy (SMA) is an autosomal recessive disorder with no present cure. Here the authors perform an in vitro screening leading to the identification of a small molecule that alters the conformational dynamics of the TSL2 RNA structure and acts as a modulator of SMN exon 7 splicing.
- Amparo Garcia-Lopez
- , Francesca Tessaro
- & Leonardo Scapozza
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Article
| Open AccessProtein polarization driven by nucleoid exclusion of DnaK(HSP70)–substrate complexes
Many bacterial proteins exhibit spatially defined localization important for function. Here the authors show that the polar localization of Shigella IpaC type III secretion substrate is mediated by its interaction with the DnaK chaperone and occlusion by the bacterial nucleoid.
- Clémence Collet
- , Jenny-Lee Thomassin
- & Guy Tran Van Nhieu
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Article
| Open AccessProbing the gating mechanism of the mechanosensitive channel Piezo1 with the small molecule Yoda1
Piezo ion channels transduce mechanical stimuli into biological signals but the underlying mechanism has remained elusive. Here, the authors use the selective agonist Yoda1 to identify molecular determinants of Piezo activation, providing mechanistic insights into Piezo-mediated mechanotransduction.
- Jerome J. Lacroix
- , Wesley M. Botello-Smith
- & Yun Luo
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Article
| Open AccessTargeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor
G protein-coupled receptors (GPCRs) activate and dissociate the G protein heterotrimer into Gα-GTP and Gβγ dimer, which facilitate distinct signalling events. Here authors develop a nanobody, Nb5 that modulates Gβγ-mediated signaling without affecting GTP-bound Gαq and Gαs-mediated signaling events.
- Sahil Gulati
- , Hui Jin
- & Krzysztof Palczewski
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Article
| Open AccessBacterial encapsulins as orthogonal compartments for mammalian cell engineering
Artificial compartments have been expressed in prokaryotes and yeast, but similar capabilities have been missing for mammalian cell engineering. Here the authors use bacterial encapsulins to engineer genetically controlled multifunctional orthogonal compartments in mammalian cells.
- Felix Sigmund
- , Christoph Massner
- & Gil G. Westmeyer
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Article
| Open AccessLight-induced formation of partially reduced oxygen species limits the lifetime of photosystem 1-based biocathodes
Photobiodevices use photosynthetic proteins such as those of the photosystem 1 (PS1) to enable light-induced charge separation, but they suffer from limited long-term stability. Here authors employ scanning photoelectrochemical microscopy on a PS1 biocathode and find that several pathways generate oxygen radicals.
- Fangyuan Zhao
- , Steffen Hardt
- & Felipe Conzuelo
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Article
| Open AccessSingle cell analysis of kynurenine and System L amino acid transport in T cells
Kynurenine is an immunomodulatory aryl hydrocarbon receptor (AHR) ligand. Here the authors show, using a new flow cytometry based method, that kynurenine needs to be transported across the plasma membrane of activated T cells by the transporter protein SLC7A5 to activate the AHR.
- Linda V. Sinclair
- , Damien Neyens
- & Doreen A. Cantrell
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Article
| Open AccessA cell-penetrating artificial metalloenzyme regulates a gene switch in a designer mammalian cell
Artificial enzymes can be used to elicit reactions in cells. Here, the authors developed such an artificial catalyst combined with a genetic switch, and showed that it was readily taken up by human cells and able to kick off a reaction cascade resulting in the biosynthesis of the desired product.
- Yasunori Okamoto
- , Ryosuke Kojima
- & Thomas R. Ward
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Article
| Open AccessEnantioselective reduction of sulfur-containing cyclic imines through biocatalysis
The 3-thiazolidine ring, a pharmaceutically interesting cyclic structural element found e.g. in some antibiotics, is hard to obtain via currently used approaches. Here, the authors developed a straightforward method to efficiently synthesize a variety of defined, pure 3-thiazolidines.
- Nadine Zumbrägel
- , Christian Merten
- & Harald Gröger
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Article
| Open AccessStructural basis for the recognition of complex-type N-glycans by Endoglycosidase S
Endoglycosidase S only recognizes one particular type of glycan within IgG antibodies but the molecular basis for this high specificity is not fully understood. Here, the authors present the crystal structure of product-bound Endoglycosidase S, revealing the determinants for its glycan specificity.
- Beatriz Trastoy
- , Erik Klontz
- & Marcelo E. Guerin
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Article
| Open AccessCO2-sensitive tRNA modification associated with human mitochondrial disease
Transfer RNA modifications play critical roles in protein synthesis. Here the authors reveal the t6A37 tRNA modification is dynamically regulated by sensing intracellular CO2 concentration in mitochondria, implying metabolic regulation of protein synthesis.
- Huan Lin
- , Kenjyo Miyauchi
- & Tsutomu Suzuki
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Article
| Open AccessStructural basis for cofilin binding and actin filament disassembly
Cofilin is a small actin-binding protein that accelerates actin turnover by disassembling actin filaments. Here the authors present the 3.8 Å cryo-EM structure of a cofilin-decorated actin filament and discuss mechanistic implications.
- Kotaro Tanaka
- , Shuichi Takeda
- & Akihiro Narita
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Article
| Open AccessBiosynthetic pathway for furanosteroid demethoxyviridin and identification of an unusual pregnane side-chain cleavage
Demethoxyviridin is a fungal steroid that inhibits a phosphatidylinositol 3-kinase, an enzyme contributing to tumor progression. Here, the authors elucidate the biosynthetic route that leads to the formation of demethoxyviridin in fungi.
- Gao-Qian Wang
- , Guo-Dong Chen
- & Hao Gao
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Article
| Open AccessFemtosecond X-ray coherent diffraction of aligned amyloid fibrils on low background graphene
The structures of amyloid fibres are currently primarily studied through solid state NMR and cryo-EM. Here the authors present a free-standing graphene support device that allows diffraction imaging of non-crystalline amyloid fibrils with single X-ray pulses from an X-ray free-electron laser.
- Carolin Seuring
- , Kartik Ayyer
- & Henry N. Chapman
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Article
| Open AccessDefining a conformational ensemble that directs activation of PPARγ
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor. Here the authors provide insights into PPARγ activation by combining fluorine (19F) NMR and molecular dynamics simulations to characterize the nuclear receptor conformational ensemble in solution and the response of this ensemble to ligand and coregulatory peptide binding.
- Ian M. Chrisman
- , Michelle D. Nemetchek
- & Travis S. Hughes
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Article
| Open AccessChemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice
Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells. Here, the authors report the development and in vivo validation of a non-internalising ADC with the capacity to target cancer cells and release its therapeutic cargo extracellularly via a chemical trigger.
- Raffaella Rossin
- , Ron M. Versteegen
- & Marc S. Robillard
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Article
| Open AccessNuclear fate of yeast snoRNA is determined by co-transcriptional Rnt1 cleavage
Small nucleolar ribonucleoprotein complexes (snoRNP) are fundamental for ribosome biogenesis. Here the authors provide insight into the 5ʹend processing of S. cerevisiae snoRNA and its important role in downstream nuclear events.
- Pawel Grzechnik
- , Sylwia A. Szczepaniak
- & Nicholas J. Proudfoot
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Article
| Open AccessHsp90 shapes protein and RNA evolution to balance trade-offs between protein stability and aggregation
It remains poorly understood whether and how chaperones control protein evolution. Here the authors show how the chaperone Hsp90 shapes the sequence space of its client, poliovirus protein P1, at the polypeptide and RNA level to balance the evolutionary trade-offs between protein stability, aggregation and translation rate.
- Ron Geller
- , Sebastian Pechmann
- & Judith Frydman
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Article
| Open AccessIdentification of a pyrophosphate-dependent kinase and its donor selectivity determinants
While most kinases are ATP-dependent some utilize pyrophosphate (PPi) instead. Here the authors structurally characterize a PPi-dependent kinase, identify its key recognition residues and find further PPi-dependent ribokinase family members with this signature pattern.
- Ryuhei Nagata
- , Masahiro Fujihashi
- & Kunio Miki
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Article
| Open AccessNon-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy
DAPK2 is a calmodulin-regulated protein kinase implicated in autophagy regulation, but how physiological stress leads to its activation is yet unknown. Here, the authors show that the central metabolic sensor AMPK phosphorylates DAPK2 to promote autophagy in a calmodulin-independent mechanism.
- Ruth Shiloh
- , Yuval Gilad
- & Adi Kimchi
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Article
| Open AccessSubstrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site
Sialic acid transporters (SiaT) are required for sialic acid uptake in a number of human pathogens and are of interest as targets for antimicrobial drug development. Here the authors present the substrate bound SiaT structure from the uropathogen Proteus mirabilis and provide insights into the mechanism of sialic acid transport.
- Weixiao Y. Wahlgren
- , Elin Dunevall
- & Rosmarie Friemann
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Article
| Open AccessArchitecture of the U6 snRNP reveals specific recognition of 3′-end processed U6 snRNA
The spliceosome removes introns from precursor messenger RNAs to produce mature mRNAs. Here the authors report a U6 snRNP crystal structure that provides insight on how the 3′ phosphate of U6 snRNA is recognized by the Lsm2–8 complex and how the U6 snRNP proteins sequester and protect the active site RNA until it is assembled into the spliceosome.
- Eric J. Montemayor
- , Allison L. Didychuk
- & Samuel E. Butcher
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