Featured
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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 AccessLptM promotes oxidative maturation of the lipopolysaccharide translocon by substrate binding mimicry
Here, the authors identify a third component of the outer membrane LPS translocon in Escherichia coli called LptM. Biochemical analysis and structural modelling reveal that LptM binds the LPS translocon by mimicking its native substrate, so stabilising an active conformation of the complex.
- Yiying Yang
- , Haoxiang Chen
- & Raffaele Ieva
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Article
| Open AccessStructure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2
SH2 domains are challenging to target using small molecules. Here, the authors develop phosphotyrosine-based covalent ligands of the E3 ligase SOCS2 using structure-based design. A pro-drug approach yields cell active inhibitors that block SOCS2 substrate recruitment.
- Sarath Ramachandran
- , Nikolai Makukhin
- & Alessio Ciulli
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Article
| Open AccessA cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation
The authors show that dynamics of protein phosphorylation in the vertebrate cell cycle is largely attributable to CDK-mediated regulation of intrinsically disordered proteins that are involved in biomolecular condensate formation.
- Juan Manuel Valverde
- , Geronimo Dubra
- & Maarten Altelaar
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Article
| Open AccessGLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics
Agonists of the glucagon-like peptide-1 receptor are used to treat diabetes and obesity. Here, Wright et al. investigate the subcellular location of the receptor’s signaling events and uncover associations between signaling profiles and adverse drug reactions.
- Shane C. Wright
- , Aikaterini Motso
- & Volker M. Lauschke
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Article
| Open AccessReversible photoregulation of cell-cell adhesions with opto-E-cadherin
Tools for high spatiotemporal control of cell-cell adhesions are lacking. Here, authors propose an optogenetic tool, opto-E-cadherin, that allows reversible control of E-cadherin-mediated cell-cell adhesions with blue light.
- Brice Nzigou Mombo
- , Brent M. Bijonowski
- & Seraphine V. Wegner
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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 AccessChemoproteomic capture of RNA binding activity in living cells
Here the authors introduce a photo-activatable-competition and chemoproteomic enrichment (PACCE) method to localize protein-RNA interfaces using photoactivatable cellular RNA to protect RNA binding regions on proteins from electrophilic purine probe labeling.
- Andrew J. Heindel
- , Jeffrey W. Brulet
- & Ku-Lung Hsu
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Article
| Open AccessFluorescent sensors for imaging of interstitial calcium
The study of interstitial calcium remains challenging due to scarce methodology. Here, authors present ultra-low affinity genetically encoded fluorescent biosensors for monitoring calcium in intercellular spaces in living tissues.
- Ariel A. Valiente-Gabioud
- , Inés Garteizgogeascoa Suñer
- & Oliver Griesbeck
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Article
| Open AccessAn autoinhibited state of 53BP1 revealed by small molecule antagonists and protein engineering
Here, using small molecule antagonists and protein engineering, the authors identify an autoinhibited state of 53BP1 leading to its chromatin binding surface being obstructed. Such small molecule ligands present a potential avenue for the development of cancer therapy drugs.
- Gaofeng Cui
- , Maria Victoria Botuyan
- & Georges Mer
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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 AccessAn amide to thioamide substitution improves the permeability and bioavailability of macrocyclic peptides
Solvent shielding of the amide hydrogen bond donor through chemical modification or conformational control has been successfully utilized to impart membrane permeability to macrocyclic peptides. Here, the authors show that passive membrane permeability can also be conferred by masking the amide hydrogen bond acceptor through thioamide substitution, leading to improved pharmacological properties of peptide macrocycles.
- Pritha Ghosh
- , Nishant Raj
- & Jayanta Chatterjee
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Article
| Open AccessThe leaderless communication peptide (LCP) class of quorum-sensing peptides is broadly distributed among Firmicutes
The human pathogen Streptococcus pyogenes secretes a short peptide (LCP) that mediates intercellular communication and controls bacterial virulence. Here, the authors show that LCP homologues act as bacterial intercellular signals and regulate gene expression also in other bacteria.
- Shifu Aggarwal
- , Elaine Huang
- & Muthiah Kumaraswami
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Article
| Open AccessStructural basis for calcium-stimulating pore formation of Vibrio α-hemolysin
Vibrio α-hemolysins (αHLs) are toxins crucial for certain bacterial infections. Here the authors reveal that calcium ions boost the activity of a specific toxin, Vibrio campbellii αHL, and uncover its calcium-dependent activation mechanism.
- Yu-Chuan Chiu
- , Min-Chi Yeh
- & Shih-Ming Lin
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Article
| Open AccessA chemical catalyst enabling histone acylation with endogenous acyl-CoA
Chemical catalysts that can promote physiologically important post-translational modifications acting as enzyme surrogates have not been reported. Here, the authors develop mBnA, a chemical catalyst that promotes histone lysine acylation in live cells by activating endogenous acyl-CoAs as the only acyl donors.
- Misuzu Habazaki
- , Shinsuke Mizumoto
- & Motomu Kanai
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Article
| Open AccessStructural basis of hydroxycarboxylic acid receptor signaling mechanisms through ligand binding
Hydroxy-carboxylic acid receptor (HCA) is an attractive drug target for neuroinflammation. Here, authors report cryo-EM structures of the HCA2 and HCA3-Gi complexes with multiple ligands, to describe the drug recognition and subtype selectivity.
- Shota Suzuki
- , Kotaro Tanaka
- & Yoshinori Fujiyoshi
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Article
| Open AccessChronic cough relief by allosteric modulation of P2X3 without taste disturbance
P2X3 activation requires tightening the inner pocket of the head domain (IP-HD) following ATP binding. Here the authors demonstrate that targeting the IP-HD with allosteric small molecules presents a potential strategy for the development of therapeutics for refractory chronic cough without taste abnormalities.
- Chang-Run Guo
- , Zhong-Zhe Zhang
- & Ye Yu
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Article
| Open AccessCustom tuning of Rieske oxygenase reactivity
Rieske oxygenase chemistry is important for biochemical pathways, but it remains elusive how a common protein scaffold can be predictively tuned to catalyze divergent reactions. Here, the authors report a strategy that can rationally tune TsaM, a Rieske monooxygenase to catalyze dioxygenation and sequential monooxygenation reactions, and customize the reactivity of other Rieske oxygenases.
- Jiayi Tian
- , Jianxin Liu
- & Jennifer Bridwell-Rabb
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Article
| Open AccessHistidine modulates amyloid-like assembly of peptide nanomaterials and confers enzyme-like activity
In this work, the authors report that Histidine residues play a critical role in modulating amyloid-like assembly and building active sites for Fmoc–F–F and Aβ aggregates. Aβ1-42 filaments were found to perform peroxidase-like activity to enhance oxidative stress, which might also be ascribed to the interaction mode of His and F-F.
- Ye Yuan
- , Lei Chen
- & Lizeng Gao
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Article
| Open AccessHost heparan sulfate promotes ACE2 super-cluster assembly and enhances SARS-CoV-2-associated syncytium formation
The molecular mechanism of syncytium formation during SARS-CoV-2 infection is not fully understood. Zhang et al. now show that cell surface heparan sulfate enhances spike-induced ACE2 clustering and cell-cell fusion, which depends on a conserved ACE2 linker and is blocked by a heparan sulfate binding drug.
- Qi Zhang
- , Weichun Tang
- & Yihong Ye
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Article
| Open AccessN-terminal α-amino SUMOylation of cofilin-1 is critical for its regulation of actin depolymerization
SUMOylation plays a key role in modulating protein function. Here, the authors uncover a form of SUMOylation, termed N-αSUMOylation, where SUMO1 attaches to the N-terminus of cofilin1. This SUMOylation promotes cofilin-1 binding to F-actin and cofilin-induced actin depolymerization.
- Weiji Weng
- , Xiaokun Gu
- & Yong Li
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Article
| Open AccessGenetically encoded discovery of perfluoroaryl macrocycles that bind to albumin and exhibit extended circulation in vivo
Peptide-based therapeutics are promising therapeutic modalities, however, their prevalent drawback is poor circulation half-life in vivo. Here, the authors report the selection of albumin-binding macrocyclic peptides from genetically encoded libraries of peptides modified by perfluoroaryl-cysteine chemistry, with decafluoro-diphenylsulfone.
- Jeffrey Y. K. Wong
- , Arunika I. Ekanayake
- & Ratmir Derda
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Article
| Open AccessMembrane manipulation by free fatty acids improves microbial plant polyphenol synthesis
The inherent toxicity of the aromatic compounds to the chassis strain hampers further improvement of bioproduction. Here, the authors show that membrane rigidifying effect of resveratrol can be attenuated by exogenous supplementation of palmitelaidic acid or linoleic acid in fermentation of Corynebacterium glutamicum.
- Apilaasha Tharmasothirajan
- , Josef Melcr
- & Jan Marienhagen
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Article
| Open AccessMultidisciplinary studies with mutated HIV-1 capsid proteins reveal structural mechanisms of lattice stabilization
The effects of E45A or P38A capsid mutations on HIV core stability and infectivity are reversed by R132T or T216I. Here, authors used structural and biophysical methods to reveal short- and long-range rearrangements that explain stability changes.
- Anna T. Gres
- , Karen A. Kirby
- & Stefan G. Sarafianos
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Article
| Open AccessChemical-induced phase transition and global conformational reorganization of chromatin
The authors show that adriamycin induces global changes on chromatin conformation associated with phase transitions mediated through Histone H1.
- Tengfei Wang
- , Shuxiang Shi
- & Chao-Po Lin
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Article
| Open AccessHeterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam
Here, the reaction of the suicide inhibitor sulbactam with the M. tuberculosis β-lactamase (BlaC) is investigated with time-resolved crystallography. Singular Value Decomposition is implemented to extract kinetic information despite changes in unit cell parameters during the time-course of the reaction.
- Tek Narsingh Malla
- , Kara Zielinski
- & Marius Schmidt
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Article
| Open AccessA cytotoxic T cell inspired oncolytic nanosystem promotes lytic cell death by lipid peroxidation and elicits antitumor immune responses
Different types of lytic cell death can trigger an anti-tumor immune response. Here the authors report the design of a near infrared light controllable micron-scale oncolytic system, triggering lipid peroxidation and lytic cell death in tumors as well anti-tumor immunity in preclinical cancer models.
- Zhigui Zuo
- , Hao Yin
- & Qinyang Wang
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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 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 AccessDNA nanopores as artificial membrane channels for bioprotonics
Synthetic membrane channels have many potential applications, but interfacing membrane channels with electronic devices for efficient information transfer is challenging. Here the authors integrate membrane spanning DNA nanopores with bioprotonic contacts to create programmable, modular, and efficient artificial ion-channel interfaces.
- Le Luo
- , Swathi Manda
- & Marco Rolandi
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Article
| Open AccessSuppression of alpha-carbon racemization in peptide synthesis based on a thiol-labile amino protecting group
During solid-phase peptide synthesis (SPPS) inherent side reactions of the protected amino acids such as α-C racemization generate by-products that are hard to remove. Here, the authors report thiol-labile amino protecting group for SPPS, DNPBS group, which suppresses the main side reactions observed during conventional SPPS.
- Yifei Zhou
- , Hongjun Li
- & Chuanzheng Zhou
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Article
| Open AccessA portable regulatory RNA array design enables tunable and complex regulation across diverse bacteria
A lack of composable and tunable gene regulators has hindered efforts to engineer nonmodel bacteria and consortia. Here the authors deliver a tunable gene regulatory platform based on RNA arrays to control gene expression across different microbes.
- Baiyang Liu
- , Christian Cuba Samaniego
- & James Chappell
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Article
| Open AccessChemoenzymatic synthesis of genetically-encoded multivalent liquid N-glycan arrays
Cellular glycosylation is complex and heterogeneous, which is challenging to reproduce synthetically. Here, the authors report on enzymatic remodelling of multivalent glycosylated bacteriophages to produce genetically encoded library of N-glycans which can be used to measure glycan-protein interactions with lectins on the surface of live cells and organs.
- Chih-Lan Lin
- , Mirat Sojitra
- & Ratmir Derda
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Article
| Open AccessCircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications
Osteoarthritis is a prevalent age-related disease. Here, the authors show that that CircRREB1 is highly expressed in second generation chondrocytes and its deficiency can alleviate FASN related senescent phenotypes and osteoarthritis progression.
- Zhe Gong
- , Jinjin Zhu
- & Shuying Shen
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Article
| Open AccessVisualizing single-molecule conformational transition and binding dynamics of intrinsically disordered proteins
Intrinsically disordered proteins (IDPs) are highly dynamic and play pivotal roles in cellular processes but can be difficult to study. Here, the authors develop a single-molecule nanocircuit for the real-time monitoring of c-Myc conformational transitions and their interaction with ligands.
- Wenzhe Liu
- , Limin Chen
- & Xuefeng Guo
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Article
| Open AccessMetal-mediated DNA strand displacement and molecular device operations based on base-pair switching of 5-hydroxyuracil nucleobases
The development of dynamic DNA nanodevices, whose configuration and function are regulated by specific chemical inputs, represents a rapidly growing area in molecular science. Herein, the authors report the concept of metal-mediated base-pair switching to induce inter- and intramolecular DNA strand displacement in a metal-responsive manner.
- Yusuke Takezawa
- , Keita Mori
- & Mitsuhiko Shionoya
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Article
| Open AccessClick-electrochemistry for the rapid labeling of virus, bacteria and cell surfaces
Methods for direct covalent ligation of microorganism surfaces are scarce. Here, the authors developed a rapid electrochemical process for the direct covalent ligation and labelling of the surfaces of virus, bacteria and cells using N-methylluminol, a fully tyrosine-selective protein anchoring group.
- Sébastien Depienne
- , Mohammed Bouzelha
- & Sébastien G. Gouin
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Article
| Open AccessAn integrated proteome and transcriptome of B cell maturation defines poised activation states of transitional and mature B cells
B cells pursue specific genetic programs to facilitate downstream cellular functions. Here the authors identify, using a combination of proteomic, transcriptomic and functional analyses, a group of mRNAs related to early activation and antibody production that are expressed in B cells without corresponding proteins, hinting a ‘poised’ state of B cells.
- Fiamma Salerno
- , Andrew J. M. Howden
- & Martin Turner
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Comment
| Open AccessEpichaperomics reveals dysfunctional chaperone protein networks
Molecular chaperones establish essential protein-protein interaction networks. Modified versions of these assemblies are generally enriched in certain maladies. A study published in Nature Communications used epichaperomics to identify unique changes occurring in chaperone-formed protein networks during mitosis in cancer cells.
- Mark R. Woodford
- , Dimitra Bourboulia
- & Mehdi Mollapour
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Article
| Open AccessPyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming
Nitric oxide has been shown to target mitochondrial aconitase 2 and pyruvate dehydrogenase to reprogramme macrophage metabolism. Here, the authors extend these findings to show that lipoate is used to generate nitroxyl in this process.
- Erika M. Palmieri
- , Ronald Holewinski
- & Daniel W. McVicar
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Article
| Open AccessMetabolic glycan labeling immobilizes dendritic cell membrane and enhances antitumor efficacy of dendritic cell vaccine
Dendritic cell (DC) vaccines were among the first FDA-approved cancer immunotherapies but have been limited by the modest therapeutic efficacy. Here, authors report a facile metabolic glycan labeling approach to improving the cytotoxic T lymphocyte response and antitumor efficacy of DC vaccines.
- Joonsu Han
- , Rimsha Bhatta
- & Hua Wang
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Article
| Open AccessLenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation
Lenalidomide is effective for treating several hematological cancers but has teratogenic effect on the fetus. Here, the authors identify modifications that make lenalidomide more selective and effective when used as a stand-alone molecular glue or integrated in PROTACs.
- Satoshi Yamanaka
- , Hirotake Furihata
- & Tatsuya Sawasaki
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Article
| Open AccessExtensive breaking of genetic code degeneracy with non-canonical amino acids
Genetic code expansion is limited by the degeneracy of the 61 sense codons which encode for only 20 amino acids. Here, the authors show that by combining hyperaccurate ribosomes and in vitro transcribed tRNAs, dramatic and extensive breaking of sense codon degeneracy can be achieved.
- Clinton A. L. McFeely
- , Bipasana Shakya
- & Matthew C. T. Hartman
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Article
| Open AccessPharmacological perturbation of the phase-separating protein SMNDC1
SMNDC1 is a splicing factor that binds arginine methylation with its Tudor domain. Here, the authors study the protein’s phase-separating behavior and develop small-molecule Tudor domain inhibitors that perturb SMNDC1 function.
- Lennart Enders
- , Marton Siklos
- & Stefan Kubicek
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Article
| Open AccessQuantitative real-time in-cell imaging reveals heterogeneous clusters of proteins prior to condensation
The nucleation of biomolecular condensates is seldom quantified in living cells. Here, the authors show how protein clusters form before microscopically visible condensation and find a flat free-energy profile with active blocking of cluster growth.
- Chenyang Lan
- , Juhyeong Kim
- & Thorsten Hugel
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Article
| Open AccessBiosensor Guided Polyketide Synthases Engineering for Optimization of Domain Exchange Boundaries
Engineering polyketide synthases can be challenging due to the absence of efficient high-throughput methods. Here, the authors used a solubility biosensor to identify stable variants from libraries of modified polyketide synthases.
- Elias Englund
- , Matthias Schmidt
- & Jay D. Keasling
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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 AccessSmall molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels
Branched chain ketoacid dehydrogenase kinase (BDK) inhibits the activity of branched chain ketoacid dehydrogenase and branched chain amino acid degradation, implicated in several diseases. Here, the authors discover a BDK inhibitor and degrader that shows efficacy in rodent metabolism and heart failure models, as well as another class of BDK inhibitors that stabilizes BDK.
- Rachel J. Roth Flach
- , Eliza Bollinger
- & Kevin J. Filipski
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