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| Open AccessCytoglobin regulates NO-dependent cilia motility and organ laterality during development
Developmental defects in left-right cardiac determination in humans are associated with ciliary dysfunction and low airway epithelial nitric oxide production. Here, the authors show that cytoglobin is essential for nitric oxide signaling, cilia function, and left-right patterning during zebrafish development.
- Elizabeth R. Rochon
- , Jianmin Xue
- & Paola Corti
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Article
| Open AccessUniKP: a unified framework for the prediction of enzyme kinetic parameters
Prediction of enzyme kinetic parameters is essential for designing and optimising enzymes for various biotechnological and industrial applications. Here, authors presented a prediction framework (UniKP), which improves the accuracy of predictions for three enzyme kinetic parameters.
- Han Yu
- , Huaxiang Deng
- & Xiaozhou Luo
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Article
| Open AccessDiscovery of type II polyketide synthase-like enzymes for the biosynthesis of cispentacin
Type II polyketide synthases (PKSs) normally synthesize polycyclic aromatic compounds, but the potential for the synthesis of further diverse skeletons remains under investigated. Here, the authors report the discovery of the type II PKS machinery for the biosynthesis of a five-membered nonaromatic skeleton contained in the nonproteinogenic amino acid cispentacin and the plant toxin coronatine.
- Genki Hibi
- , Taro Shiraishi
- & Tomohisa Kuzuyama
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Article
| Open AccessIlluminating the mechanism and allosteric behavior of NanoLuc luciferase
NanoLuc luciferase is a popular bioluminescent enzyme, but the molecular details of its mechanism of action on luciferins such as coelenterazine remained elusive. Here the authors use, protein crystal structures and biochemical analyses to provide an atomistic description of its catalytic mechanism and allosteric behaviour.
- Michal Nemergut
- , Daniel Pluskal
- & Martin Marek
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Article
| Open AccessMolecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2)
Neutral sphingomyelinases play pivotal roles in ceramide-related signaling transduction. Here, the authors solve the structure of human neutral sphingomyelinase SMPD2 and propose a catalytic mechanism, potentially enhancing understanding of ceramide in disease and cancer treatment.
- Jingbo Yi
- , Boya Qi
- & Maojun Yang
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Matters Arising
| Open AccessGAS2 encodes a 2-oxoglutarate dependent dioxygenase involved in ABA catabolism
- Theo Lange
- , Nadiem Atiq
- & Maria João Pimenta Lange
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Article
| Open AccessFunctional annotation of enzyme-encoding genes using deep learning with transformer layers
Functional annotation of open reading frames in microbial genomes remains substantially incomplete. Here, Kim et al. present a deep learning model that utilizes transformer layers as a neural network architecture to predict specific catalytic functions for enzyme-encoding genes of unknown function.
- Gi Bae Kim
- , Ji Yeon Kim
- & Sang Yup Lee
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Article
| Open AccessA 5+1 assemble-to-activate mechanism of the Lon proteolytic machine
Many AAA+ (ATPases associated with diverse cellular activities) proteins function as a hexamer to remodel protein substrates. Here, the authors report the discovery of a pentameric form of the Lon AAA+ protease and show that it plays a role in the substrate-dependent activation of the AAA+ protein.
- Shanshan Li
- , Kan-Yen Hsieh
- & Chung-I Chang
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Article
| Open AccessBiosynthesis of barley wax β-diketones: a type-III polyketide synthase condensing two fatty acyl units
Barley plants coat their organs with waxy diketones to protect against late-summer droughts. These diketones are formed by two enzymes, one diverting common fatty acids from normal metabolism and the other one linking two fatty acid units together.
- Yulin Sun
- , Alberto Ruiz Orduna
- & Reinhard Jetter
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Article
| Open AccessCoordinated regulation of the entry and exit steps of aromatic amino acid biosynthesis supports the dual lignin pathway in grasses
The study by El-Azaz et al. uncovers how grasses fine-tune tyrosine and phenylalanine production to support their unique dual entry pathway to lignin and phenylpropanoids. The findings help improve sustainable production of aromatic chemicals in crops.
- Jorge El-Azaz
- , Bethany Moore
- & Hiroshi A. Maeda
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Article
| Open AccessEnzymatic β-elimination in natural product O- and C-glycoside deglycosylation
Biological degradation of glycosides involves, alongside hydrolysis, β-elimination for glycosidic bond cleavage. Here, the authors report an O-glycoside β-eliminase from Agrobacterium tumefaciens that converts the C3-oxidized O-β-d-glucoside of phloretin into the aglycone and the 2-hydroxy-3-keto-d-glycal elimination product, and suggest convergent evolution of β-eliminase active sites for the cleavage of natural product 3-keto-O-glycosides.
- Johannes Bitter
- , Martin Pfeiffer
- & Bernd Nidetzky
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Article
| Open AccessCatalytically inactive long prokaryotic Argonaute systems employ distinct effectors to confer immunity via abortive infection
Here, Song et al. show that catalytically inactive long prokaryotic Argonaute proteins are equipped with distinct effectors that are activated upon recognition of invading genetic elements to trigger cell death and confer abortive infection immunity.
- Xinmi Song
- , Sheng Lei
- & Wenyuan Han
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Article
| Open AccessRecognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides
Identification of molecules that induce novel interactions between proteins has been limited by the complexity of rationally designing interactions. The authors report a method to discover molecular glue-like “trimerizers” based on α-helically constrained peptides that can co-opt the surfaces of E3 ubiquitin ligases to bind therapeutically important proteins.
- Olena S. Tokareva
- , Kunhua Li
- & John H. McGee
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Article
| Open AccessA genome-scale metabolic model of parasitic whipworm
In this work, Bay et al describe the construction of the first genome-scale metabolic model for the parasitic whipworm, Trichuris muris and use it to identify novel metabolic pathways and predict critical enzymes and essential metabolites for worm survival.
- Ömer F. Bay
- , Kelly S. Hayes
- & Ian S. Roberts
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Article
| Open AccessTandem-biocatalysis reactors constructed by topological evolution of CaCO3 particles into hollow metal hydroxide spheres
Hollow inorganic spheres (HISs) hold potential in various technological areas including biocatalysis and biomedicine, but the harsh synthetic conditions have precluded the use of HISs in biological fields. Here, the authors report a biocompatible strategy for synthesizing metal hydroxide HISs that can function as tandem-biocatalytic reactors.
- Sang Yeong Han
- , Nayoung Kim
- & Insung S. Choi
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Article
| Open AccessLactate dehydrogenase D is a general dehydrogenase for D-2-hydroxyacids and is associated with D-lactic acidosis
Currently the structure and biological function of Lactate Dehydrogenase D (LDHD) are unclear. Here the authors report the structure of LDHD bound with various ligands and show that LDHD is a general dehydrogenase for D-2-hydroxyacids with small to moderate-size hydrophobic moieties and investigate loss-of-function mutations that play an important role in D-lactic acidosis.
- Shan Jin
- , Xingchen Chen
- & Jianping Ding
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Article
| Open AccessStructural basis for the unique molecular properties of broad-range phospholipase C from Listeria monocytogenes
The bacterium Listeria monocytogenes possesses two major virulence factors, broad-range phospholipase C (LmPC-PLC) and the pore-forming toxin listeriolysin O (LLO). Here, authors perform structural and biochemical analysis of LmPC-PLC and show that unique structural features enable self-regulation of its enzymatic activity and positive synergy with the pore-forming toxin listeriolysin O.
- Nejc Petrišič
- , Maksimiljan Adamek
- & Marjetka Podobnik
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Article
| Open AccessMolecular mechanism of decision-making in glycosaminoglycan biosynthesis
Heparan sulfate (HS) and chondroitin sulfate (CS) are different glycosaminoglycan chains that are attached to core proteins via the same linker tetrasaccharide, and it was unclear how core proteins are specifically modified with HS or CS. Here, the authors determine that the CS-initiating glycosyltransferase CSGALNACT2 is promiscuous, whereas the HS-initiating glycosyltransferase EXTL3 selects only certain core proteins for modification.
- Douglas Sammon
- , Anja Krueger
- & Erhard Hohenester
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Article
| Open AccessStructure of full-length cobalamin-dependent methionine synthase and cofactor loading captured in crystallo
Methionine synthase (MS) harnesses B12 and flexibility to catalyze three different reactions on one protein. The full-length structure of MS yields insights into a protein that epitomizes controlled dynamics to dictate chemical outcome.
- Johnny Mendoza
- , Meredith Purchal
- & Markos Koutmos
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Article
| Open AccessTriepoxide formation by a flavin-dependent monooxygenase in monensin biosynthesis
MonCI, a flavin-dependent monooxygenase, transforms all three C = C groups in the polyene substrate into epoxides during monensin A biosynthesis. Here, the authors present the structural basis for this enzyme’s regio- and stereoselective epoxidation activity.
- Qian Wang
- , Ning Liu
- & Chu-Young Kim
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Article
| Open AccessAcetylation-dependent coupling between G6PD activity and apoptotic signaling
Lysine acetylation is highly prevalent in metabolic enzymes. Here, the authors highlight the diverse roles of acetylation and show that G6PD acetylation can activate/deactivate G6PD, and promote G6PD ubiquitylation and phosphorylation, its interaction with p53, and p53-dependent pro-apoptotic events.
- Fang Wu
- , Natali H. Muskat
- & Eyal Arbely
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Article
| Open AccessAutoantibody binding and unique enzyme-substrate intermediate conformation of human transglutaminase 3
Dermatitis herpetiformis, a skin manifestation of the gluten-sensitive condition celiac disease, is hallmarked by autoantibody production to transglutaminase 3. Here, the authors present the 3D-structures of an autoantibody bound to transglutaminase 3 with an inhibitor mimicking a gluten-peptide substrate.
- Julie Elisabeth Heggelund
- , Saykat Das
- & Ludvig M. Sollid
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Article
| Open AccessComputational remodeling of an enzyme conformational landscape for altered substrate selectivity
The ability to rationally remodel enzyme conformational landscapes to modify catalytic properties is limited. Here, the authors, using a computational procedure, redesign the conformational landscape of an aminotransferase to stabilize a less populated but reactive conformation and thereby increase catalytic efficiency with a non-native substrate.
- Antony D. St-Jacques
- , Joshua M. Rodriguez
- & Roberto A. Chica
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Article
| Open AccessCharacterization and structure-based protein engineering of a regiospecific saponin acetyltransferase from Astragalus membranaceus
Currently little is known about the acetylation on sugar moieties. Here the authors report a saponin acetyltransferase from Astragalus membranaceus, AmAT7-3, and utilise crystal structures and QM/MM computation to elucidate the catalytic mechanism: they generate mutants for specific site acetylation.
- Linlin Wang
- , Zhihui Jiang
- & Xue Qiao
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Article
| Open AccessStructure of the peroxisomal Pex1/Pex6 ATPase complex bound to a substrate
The AAA ATPase Pex1/Pex6 fuels the enzyme import across the peroxisomal membrane. Defects in either ATPase in humans result in severe disorders and early death. Here, the authors provide a detailed cryo-EM structures of the complex in the process of translocating an endogenous substate.
- Maximilian Rüttermann
- , Michelle Koci
- & Christos Gatsogiannis
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Article
| Open AccessMolecular basis for bacterial N-glycosylation by a soluble HMW1C-like N-glycosyltransferase
NGTs glycosylate asparagine residues in proteins, crucial for bacterial adhesion and pathogenicity. Here, the authors provide insights via crystallography and simulations, showing acceptor asparagine uses imidic form for catalysis and UDP-glucose phosphate group acts as general base.
- Beatriz Piniello
- , Javier Macías-León
- & Ramon Hurtado-Guerrero
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Article
| Open AccessStructural insights into functional properties of the oxidized form of cytochrome c oxidase
Using resonance Raman spectroscopy and serial femtosecond X-ray crystallography, the authors show the heme a3 iron and CuB in the resting oxidized form of Cytochrome c Oxidase are coordinated by a hydroxide ion and a water molecule, respectively.
- Izumi Ishigami
- , Raymond G. Sierra
- & Denis L. Rousseau
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Article
| Open AccessClass III hybrid cluster protein homodimeric architecture shows evolutionary relationship with Ni, Fe-carbon monoxide dehydrogenases
Here, the authors present an X-ray crystal structure of a class III hybrid cluster protein (HCP), structurally similar to Ni, Fe-carbon monoxide dehydrogenases (CODHs), enabling conclusions to be drawn regarding the structural evolution of HCP/CODH superfamily.
- Takashi Fujishiro
- & Kyosei Takaoka
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Article
| Open AccessThe H163A mutation unravels an oxidized conformation of the SARS-CoV-2 main protease
SARS-CoV-2 main protease adapts a disulfide bonded inactive state to escape oxidative stress. Here, the authors report a crystal structure of an inactive conformation of the enzyme achieved through a H163A mutation, and the mechanistic details of conformational changes using atomistic simulations.
- Norman Tran
- , Sathish Dasari
- & Aravindhan Ganesan
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Article
| Open AccessMolecular architecture and electron transfer pathway of the Stn family transhydrogenase
Acetogenic bacteria deploy electron-bifurcating transhydrogenase for electron carrier adjustments in the ancient Wood-Ljungdahl pathway. Here, the authors report a cryo-EM structure of the Stn class transhydrogenase from the Sporomusa ovata and dissect its electron transfer pathway.
- Anuj Kumar
- , Florian Kremp
- & Jan M. Schuller
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Article
| Open AccessTailored photoenzymatic systems for selective reduction of aliphatic and aromatic nitro compounds fueled by light
The selective enzymatic reduction of nitroaliphatic and nitroaromatic compounds is challenging. Here, the authors report selective (sun)light-driven photoenzymatic reduction of a wide variety of nitro compounds to aliphatic amines and amino-, azoxy- and azo-aromatics using flavin-dependent nitroreductases and chlorophyll as photocatalyst
- Alejandro Prats Luján
- , Mohammad Faizan Bhat
- & Gerrit J. Poelarends
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Article
| Open AccessProgrammable RNA detection with CRISPR-Cas12a
Cas12a is widely used in diagnostic platforms. Here the authors show that Cas12a can be programmed to directly detect RNA substrates, this is due to the 3’-end of the crRNA tolerating both RNA and DNA substrates: they use this to report a method, SAHARA, to detect RNA sequences.
- Santosh R. Rananaware
- , Emma K. Vesco
- & Piyush K. Jain
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Article
| Open AccessO-methyltransferase-like enzyme catalyzed diazo installation in polyketide biosynthesis
Diazo compounds, such as kinamycin, are rare bioactive natural products whose assembly has been extensively studied, but the formation of the diazo group is elusive. Here, the authors report O-methyltransferase-like protein, AlpH, which is responsible for the l-glutamylhydrazine incorporation in kinamycin biosynthesis.
- Yuchun Zhao
- , Xiangyang Liu
- & Ming Jiang
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Article
| Open AccessElectrostatic interactions guide substrate recognition of the prokaryotic ubiquitin-like protein ligase PafA
Pupylation is the bacterial equivalent of ubiquitination. Here, the authors show selective binding of the Pup ligase PafA to substrates is driven by tertiary structure features rather than linear motifs and is achieved by a small number of electrostatic interactions, enabling quick adaption to new substrates.
- Matthias F. Block
- , Cyrille L. Delley
- & Eilika Weber-Ban
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Article
| Open AccessA synthetic cell-free 36-enzyme reaction system for vitamin B12 production
Adenosylcobalamin (AdoCbl) is an essential vitamin whose production is limited to bacterial fermentation. Here, the authors report an alternative method for the synthesis of AdoCbl based on a cell-free reaction system integrating more than 30 biocatalytic reactions to produce AdoCbl from 5-aminolevulinic acid.
- Qian Kang
- , Huan Fang
- & Dawei Zhang
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Article
| Open AccessCrystal structure and functional implications of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases
Here, the authors present structural and functional characterization of bacterial CD-NTases that synthesize cyclic dipyrimidines for phage resistance, revealing a (R/Q)xW motif dictating pyrimidine selection which suggests a sequential pathway for synthesizing 2’3’-cyclic di-UMP.
- Chia-Shin Yang
- , Tzu-Ping Ko
- & Yeh Chen
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Article
| Open AccessDeSUMOylation of a Verticillium dahliae enolase facilitates virulence by derepressing the expression of the effector VdSCP8
Verticillium dahliae, a soil-borne fungal pathogen, causes vascular wilt in a wide variety of economically important crops. This study reveals a sophisticated pathogenic mechanism of VdUlpB-deSUMOylated enolase to facilate fungal virulence by derepressing the expression of the effector VdSCP8.
- Xue-Ming Wu
- , Bo-Sen Zhang
- & Hui-Shan Guo
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Article
| Open AccessHigh resolution cryo-EM and crystallographic snapshots of the actinobacterial two-in-one 2-oxoglutarate dehydrogenase
The 2-oxoglutarate dehydrogenase complex (ODH) is a textbook example of multienzymatic machinery. Here, the authors report the structural and regulatory properties of the Actinobacterial enzyme OdhA, a fusion of two ODH components acting in a supercomplex with pyruvate dehydrogenase.
- Lu Yang
- , Tristan Wagner
- & Marco Bellinzoni
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Article
| Open AccessStructure and regulation of full-length human leucine-rich repeat kinase 1
Leucine-rich repeat kinase 1 (LRRK1) and its counterpart LRRK2 play crucial roles in regulating fundamental cellular processes. Here, the authors use cryo-EM to characterize the LRRK1 monomer and dimer, revealing interfaces that regulate kinase activity and structural differences to LRRK2.
- Riley D. Metcalfe
- , Juliana A. Martinez Fiesco
- & Ping Zhang
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Article
| Open AccessAuranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes
Decreased activity of the E1 ubiquitin-activating enzyme UBA1 can contribute to aging and diseases like Alzheimer’s and VEXAS syndrome. Here, the authors found that auranofin, a rheumatoid arthritis drug, can significantly boost UBA1 activity.
- Wenjing Yan
- , Yongwang Zhong
- & Shengyun Fang
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Article
| Open AccessCatalytic site flexibility facilitates the substrate and catalytic promiscuity of Vibrio dual lipase/transferase
Vibrio dual lipases/transferases are virulence-related enzymes, with both substrate and catalytic promiscuity. Wang et al reveal their prominent structural flexibility, proposing a catalytic site tuning mechanism underlying enzyme promiscuity.
- Chongyang Wang
- , Changshui Liu
- & Qingjun Ma
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Article
| Open AccessProteomics and constraint-based modelling reveal enzyme kinetic properties of Chlamydomonas reinhardtii on a genome scale
Closing a major gap in photosynthetic metabolic modelling, the authors provide over 500 estimates of in vivo enzyme catalytic rate in C. reinhardtii, which considerably improves predictions on how enzyme mass is allocated to different pathways.
- Marius Arend
- , David Zimmer
- & Zoran Nikoloski
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Article
| Open AccessStructure of lasso peptide epimerase MslH reveals metal-dependent acid/base catalytic mechanism
MslH, encoded in the MS-271 biosynthetic gene cluster, catalyzes the epimerization at the Cα center of the MslA C-terminal Trp21, however, the detailed catalytic process was unknown. Here, the authors report MslH is a metallo-dependent peptide epimerase with a calcineurin-like fold.
- Yu Nakashima
- , Atsushi Kawakami
- & Hiroyuki Morita
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Article
| Open AccessThe Ycf48 accessory factor occupies the site of the oxygen-evolving manganese cluster during photosystem II biogenesis
The Ycf48 accessory factor is important for the assembly and repair of the photosystem II (PSII) complex of oxygenic photosynthesis. Here, the authors show that Ycf48 occupies the binding site of the oxygen evolving Mn cluster early in PSII biogenesis.
- Ziyu Zhao
- , Irene Vercellino
- & Josef Komenda
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Article
| Open AccessDiscovery and rational engineering of PET hydrolase with both mesophilic and thermophilic PET hydrolase properties
Extensive research efforts have been directed towards the development of PET hydrolases with improved activity, but template enzymes used are limited. Here, the authors report a PET hydrolase from Cryptosporangium aurantiacum (CaPETase) that exhibits high thermostability and PET degradation activity at ambient temperatures and determine its crystal structure.
- Hwaseok Hong
- , Dongwoo Ki
- & Kyung-Jin Kim
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Article
| Open AccessStructural and functional fine mapping of cysteines in mammalian glutaredoxin reveal their differential oxidation susceptibility
Glutaredoxin (GLRX) is a key enzyme in redox regulation via oxidation of protein cysteines and its activity is disrupted in diverse human diseases. This study integrates molecular modeling and biochemical validation to provide insights into the mechanisms of oxidative inactivation of GLRX.
- Elizabeth M. Corteselli
- , Mona Sharafi
- & Yvonne M. W. Janssen-Heininger
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Article
| Open AccessA small molecule inhibitor of PTP1B and PTPN2 enhances T cell anti-tumor immunity
Here, the authors demonstrate that inhibition of PTP1B and PTPN2 in tumor cells and T-cells with a small molecule inhibitor represses the growth of immunogenic and cold tumors, and enhances response to anti-PD-1 immunotherapy without promoting immune-related toxicities.
- Shuwei Liang
- , Eric Tran
- & Tony Tiganis
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Article
| Open AccessThe Gram-positive bacterium Romboutsia ilealis harbors a polysaccharide synthase that can produce (1,3;1,4)-β-d-glucans
(1,3;1,4)-β-d-Glucans are widely distributed in many organisms, but little is known about the enzymes responsible for their synthesis outside the grasses. Here, the authors report on the presence of (1,3;1,4)-β-d-glucans in the exopolysaccharides of the Gram-positive bacterium Romboutsia ilealis and identify and characterize the (1,3;1,4)-β-d-glucan synthase RiGT2.
- Shu-Chieh Chang
- , Mu-Rong Kao
- & Yves S. Y. Hsieh
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Article
| Open AccessRAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles
In this study, the authors present structures and functional analyses for the RAD51C-XRCC3 tumor suppressor complex, providing insights into recurrent mutations in cancer and Fanconi Anemia patients that uncover distinct DNA replication fork protection, restart and reversal regions.
- Michael A. Longo
- , Sunetra Roy
- & Katharina Schlacher