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| Open AccessCyclic 5-membered disulfides are not selective substrates of thioredoxin reductase, but are opened nonspecifically
Cyclic five-membered disulfides (1,2-dithiolanes) have been reported either as nonspecific redox motifs, or as highly specific cellular probes for thioredoxin reductase (TrxR). Here the authors show that 1,2-dithiolane probes are nonspecifically reduced by a range of thiol reductants and are not sensitive to TrxR modulation, thus they are unsuitable as cellular probes for TrxR.
- Jan G. Felber
- , Lena Poczka
- & Oliver Thorn-Seshold
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Article
| Open AccessCharacterization of protein unfolding by fast cross-linking mass spectrometry using di-ortho-phthalaldehyde cross-linkers
Conformations sampled by a protein while it unfolds are difficult to visualize. Here, the authors develop di-ortho-phthalaldehyde cross-linkers for rapid chemical cross-linking mass spectrometry analysis and demonstrate that this method captures the conformations of protein unfolding intermediates.
- Jian-Hua Wang
- , Yu-Liang Tang
- & Xiaoguang Lei
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Article
| Open AccessThe AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system
Targeted protein degradation is a promising approach for basic research and therapeutic applications. Here, the authors develop a targeted protein degradation platform called AUTOTAC to degrade oncoproteins and neurodegeneration-associated proteins via the p62-dependent autophagy-lysosome system.
- Chang Hoon Ji
- , Hee Yeon Kim
- & Yong Tae Kwon
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Article
| Open AccessUnprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction
Strategies capable of stapling unprotected peptides in a straightforward, chemoselective, and clean manner, as well as promoting cellular uptake are of great interest. Here the authors report a peptide macrocyclization and stapling strategy which satisfies those criteria, based on a fluorine thiol displacement reaction.
- Md Shafiqul Islam
- , Samuel L. Junod
- & Rongsheng E. Wang
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Article
| Open AccessLight-mediated discovery of surfaceome nanoscale organization and intercellular receptor interaction networks
The spatial organization of cell surface receptors is critical for cell signaling and drug action. Here, the authors develop an optoproteomic method for mapping surface protein interactions, revealing cellular responses to antibodies, drugs and viral particles as well as immunosynapse signaling events.
- Maik Müller
- , Fabienne Gräbnitz
- & Bernd Wollscheid
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Article
| Open AccessEngineering of a fluorescent chemogenetic reporter with tunable color for advanced live-cell imaging
Fluorescent reporters spanning the visible spectrum are needed for imaging live cells and organisms. Here the authors report a collection of fluorogenic chromophores that cover the visible spectrum from blue to red using a single engineered and optimised protein tag.
- Hela Benaissa
- , Karim Ounoughi
- & Arnaud Gautier
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Article
| Open AccessA comparative analysis of cell surface targeting aptamers
Aptamers could potentially be widely used in therapy and diagnostics. Here the authors use standardised assay conditions to compare aptamer properties in tumour targeting.
- Linsley Kelly
- , Keith E. Maier
- & Matthew Levy
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Article
| Open AccessA chemical probe based on the PreQ1 metabolite enables transcriptome-wide mapping of binding sites
The small modified nucleotide PreQ1 binds to the PreQ1 riboswitch and regulates gene expression by inducing RNA conformation change. Here the authors design and characterize a specific preQ1-derived probe by x-ray crystallography, mass spectral analysis and transcriptome-wide using Chem-CLIP.
- Sumirtha Balaratnam
- , Curran Rhodes
- & John S. Schneekloth Jr
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Article
| Open AccessChemical proteomic profiling reveals protein interactors of the alarmones diadenosine triphosphate and tetraphosphate
Diadenosine polyphosphates (ApAs) are involved in cellular stress signaling but only a few molecular targets have been characterized so far. Here, the authors develop ApnA-based photoaffinity-labeling probes and use them to identify Ap3A and Ap4A binding proteins in human cell lysates.
- Lena Krüger
- , Christoph J. Albrecht
- & Andreas Marx
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Article
| Open AccessWdr1 and cofilin are necessary mediators of immune-cell-specific apoptosis triggered by Tecfidera
The mechanism-of-action of many electrohilic drugs remains poorly understood. Here, the authors use a redox-targeting approach to elucidate the basis for the innate immune cell toxicity of dimethyl fumarate, showing that it modifies Keap1 to trigger mitochondrial-targeted neutrophil/macrophage apoptosis.
- Jesse R. Poganik
- , Kuan-Ting Huang
- & Yimon Aye
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Article
| Open AccessCellular model system to dissect the isoform-selectivity of Akt inhibitors
Elucidating specific effects of protein kinase Akt isoforms remains challenging. Here, the authors establish an Akt isoform-dependent cellular model system and use it, together with X-ray crystallography and structure-based ligand design, to develop isoform-selective covalent-allosteric Akt inhibitors
- Lena Quambusch
- , Laura Depta
- & Daniel Rauh
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Article
| Open AccessChemical tools for epichaperome-mediated interactome dysfunctions of the central nervous system
Here, the authors show structural, biochemical, and functional insights into the discovery of epichaperome‐ directed chemical probes for use in central nervous system diseases. Probes emerging from this work have translated to human clinical studies in Alzheimer’s disease and cancer.
- Alexander Bolaender
- , Danuta Zatorska
- & Gabriela Chiosis
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Article
| Open AccessMechanistic insights into the three steps of poly(ADP-ribosylation) reversal
PARG and ARH3 are the main hydrolases to reverse serine poly(ADP-ribosylation) yet their activities in the process differ. Here, the authors synthesise linear and branched poly(ADP-ribose) molecules, perform structure-function analysis and elucidate the mechanistic differences between PARG and ARH3.
- Johannes Gregor Matthias Rack
- , Qiang Liu
- & Ivan Ahel
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Article
| Open Access9-Cyanopyronin probe palette for super-multiplexed vibrational imaging
The authors develop a method to build Manhattan Raman Scattering (MARS) probes based on different core atoms, conjugation ring numbers, and stable isotope substitutions. A quantitative model predicts vibrational frequencies of MARS dyes from structures, which are used in supermultiplexed vibrational imaging.
- Yupeng Miao
- , Naixin Qian
- & Wei Min
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Article
| Open AccessPrecise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin
Photocaged molecules have advantages in terms of temporal and spatial control compared to conventional pharmacological compounds. The authors present a synthetic saxitoxin derivative affixed to a photocleavable group for precise modulation of Na channels.
- Anna V. Elleman
- , Gabrielle Devienne
- & J. Du Bois
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Article
| Open AccessAlgebraic graph-assisted bidirectional transformers for molecular property prediction
Despite considerable efforts, quantitative prediction of various molecular properties remains a challenge. Here, the authors propose an algebraic graph-assisted bidirectional transformer, which can incorporate massive unlabeled molecular data into molecular representations via a self-supervised learning strategy and assisted with 3D stereochemical information from graphs.
- Dong Chen
- , Kaifu Gao
- & Feng Pan
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Article
| Open AccessIntracellular artificial supramolecules based on de novo designed Y15 peptides
Self-assembling peptides (SAPs) can be used to build biomaterials, but genetically encoded SAPs have rarely been used as building blocks in cells. Here, the authors design a SAP that can be genetically fused to target proteins to induce their intracellular clustering and modulate their signaling functions.
- Takayuki Miki
- , Taichi Nakai
- & Hisakazu Mihara
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Article
| Open AccessReversible modulation of circadian time with chronophotopharmacology
The circadian clock is an internal mechanism that controls various physiological processes, such as the sleep-wake cycle, but its precise regulation is challenging. Here, the authors develop a visible light-responsive inhibitor of casein kinase I which controls the period and phase of cellular and tissue circadian rhythms in a reversible manner.
- Dušan Kolarski
- , Carla Miró-Vinyals
- & Ben L. Feringa
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Article
| Open AccessSpecificity of AMPylation of the human chaperone BiP is mediated by TPR motifs of FICD
The ER chaperone BiP is critical for the unfolded protein response and tightly regulated through reversible AMPylation by FICD, but the structural basis is unknown. Here the authors use thiol-reactive nucleotide derivatives to stabilize the transient FICD:BiP complex and determine its crystal structure.
- Joel Fauser
- , Burak Gulen
- & Aymelt Itzen
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Article
| Open AccessPhotoactivatable metabolic warheads enable precise and safe ablation of target cells in vivo
Metabolites can distinguish pathogenic from healthy cells, but they are hard to couple to current photosensitizers without altering their biological activity. Here the authors design a new family of photosensitizers that retain metabolite function to target pathogenic cells and ablate them by photodynamic therapy.
- Sam Benson
- , Fabio de Moliner
- & Marc Vendrell
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Article
| Open AccessKinesin-1 activity recorded in living cells with a precipitating dye
Monitoring the activity of the processive motor protein kinesin-1 in live cells is currently difficult. Here the authors report the fluorogenic small molecule QPD-OTf, a kinesin-1 substrate that causes activity-dependent dye precipitation.
- Simona Angerani
- , Eric Lindberg
- & Nicolas Winssinger
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Article
| Open AccessCalculating metalation in cells reveals CobW acquires CoII for vitamin B12 biosynthesis while related proteins prefer ZnII
The connection between metal binding to proteins and availabilities of different metals in cells has been unclear. Here, the authors report a metalation-calculator that takes into account competition between metals and their variable accessibility, and thereby elucidate in vivo metal occupancies of three different proteins, CobW, YeiR and YjiA.
- Tessa R. Young
- , Maria Alessandra Martini
- & Nigel J. Robinson
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Article
| Open AccessMutant-selective degradation by BRAF-targeting PROTACs
Hundreds of BRAF mutations have been identified in patients with cancer but currently approved drugs only target BRAF V600 mutants. Here, the authors develop a vemurafenib-based PROTAC that induces degradation of all classes of BRAF mutants without affecting wild-type RAF proteins.
- Shanique Alabi
- , Saul Jaime-Figueroa
- & Craig M. Crews
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Article
| Open AccessLigand-directed two-step labeling to quantify neuronal glutamate receptor trafficking
The analysis of AMPA-type glutamate receptor (AMPAR) trafficking is essential for understanding molecular mechanisms of learning and memory, but the analytical tools are currently limited. Here, the authors report a method that combines affinity-based receptor labeling and bioorthogonal click chemistry to quantify AMPAR distribution and trafficking under physiological conditions.
- Kento Ojima
- , Kazuki Shiraiwa
- & Shigeki Kiyonaka
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Article
| Open AccessA synthetic BRET-based optogenetic device for pulsatile transgene expression enabling glucose homeostasis in mice
Pulsing cellular dynamics in genetic circuits have been shown to provide critical capabilities to cells in diverse cellular activities. Here the authors show a synthetic BRET-based transgene expression system that allows pulsatile and quantitative activation of gene expression both in live cells and in vivo.
- Ting Li
- , Xianjun Chen
- & Yi Yang
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Article
| Open AccessAnalysing the mechanism of mitochondrial oxidation-induced cell death using a multifunctional iridium(III) photosensitiser
Mitochondrial oxidation-induced cell death is an important physiological process activated by cancer therapeutics, but its investigation is challenging. Here, the authors report a multifunctional iridium(III) photosensitiser, Ir-OA, able to induce mitochondrial oxidative stress and monitor the corresponding changes in mitochondrial properties.
- Chaiheon Lee
- , Jung Seung Nam
- & Tae-Hyuk Kwon
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Article
| Open AccessSpatiotemporal profiling of cytosolic signaling complexes in living cells by selective proximity proteomics
APEX-based proximity labeling allows capturing protein interaction dynamics but its high labeling background limits its utility for cytosolic proteins. Here, the authors develop more selective proximity labeling probes, enabling the APEX-based characterization of time-resolved cytosolic protein interactomes.
- Mi Ke
- , Xiao Yuan
- & Ruijun Tian
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Article
| Open AccessBiomimetic α-selective ribosylation enables two-step modular synthesis of biologically important ADP-ribosylated peptides
ADP-ribosylated peptides are important molecular tools, however, the lack of effective synthetic methods hinders the access to their complex structures. Here, the authors present a biomimetic α-selective ribosylation reaction coupled with click chemistry ultimately providing a two-step modular synthesis of α-ADP-ribosylated peptides.
- Anlian Zhu
- , Xin Li
- & Lingjun Li
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Article
| Open AccessLight-induced primary amines and o-nitrobenzyl alcohols cyclization as a versatile photoclick reaction for modular conjugation
Developing new click chemistry reactions for robust molecular assembly remains challenging. Here the authors report a light-induced primary amines and o-nitrobenzyl alcohols photoclick cyclization for rapid and modular functionalization of small molecules and native biomolecules, in vitro and in living systems.
- An-Di Guo
- , Dan Wei
- & Xiao-Hua Chen
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Article
| Open AccessRapid and direct control of target protein levels with VHL-recruiting dTAG molecules
The dTAG system is used to rapidly deplete tagged target proteins in vitro and in vivo, but there are context- and protein-specific differences in its effectiveness. Here, the authors develop a second generation dTAG molecule that can degrade previously recalcitrant target proteins in cells and mice.
- Behnam Nabet
- , Fleur M. Ferguson
- & Nathanael S. Gray
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Article
| Open AccessPhotoswitchable paclitaxel-based microtubule stabilisers allow optical control over the microtubule cytoskeleton
Light-based modulation of the microtubule (MT) cytoskeleton is an attractive goal for spatiotemporally-resolved MT studies. Here the authors develop a first generation photoswitchable small molecule MT stabiliser based on paclitaxel, allowing optical control over cellular MT dynamics.
- Adrian Müller-Deku
- , Joyce C. M. Meiring
- & Oliver Thorn-Seshold
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Article
| Open AccessEngineering designer beta cells with a CRISPR-Cas9 conjugation platform
Cas9 fusions partners are often limited to natural polypeptide chains at the Cas9 termni. Here the authors present a platform for site-specific and multiple-site conjugation to both termini and internal sites of Cas9, and they apply this platform to efficiently engineer insulin-producing β cells.
- Donghyun Lim
- , Vedagopuram Sreekanth
- & Amit Choudhary
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Article
| Open AccessChemical proteomics tracks virus entry and uncovers NCAM1 as Zika virus receptor
The mechanism underlying the cellular entry of Zika virus is not fully understood. Here, the authors use a chemically modified virus and time-resolved proteomics to capture interacting host proteins during virus entry and identify NCAM1 as a ZIKV receptor.
- Mayank Srivastava
- , Ying Zhang
- & W. Andy Tao
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Article
| Open AccessA potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS
Targeted protein degradation is an attractive therapeutic strategy to deplete oncogenic proteins in tumours. Here the authors demonstrate the specific targeting of endogenous KRAS protein for degradation from cancer cells, and regression of tumours expressing mutant KRAS in a mouse model.
- Nicolas Bery
- , Ami Miller
- & Terry Rabbitts
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Article
| Open AccessChemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis
Chemical tools to monitor drug-target engagement of endogenous enzymes are essential for preclinical target validation. Here, the authors present a chemical genetics strategy to study target engagement of endogenous kinases, achieving specific labeling and inactivation of FES kinase to provide insights into FES’ role in neutrophil phagocytosis.
- Tom van der Wel
- , Riet Hilhorst
- & Mario van der Stelt
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Article
| Open AccessMass spectrometry reveals the chemistry of formaldehyde cross-linking in structured proteins
Formaldehyde (FA) is a popular cross-linking reagent, but applying it for cross-linking mass spectrometry (XLMS) has been largely unsuccessful. Here, the authors show that cross-links in structured proteins are the product of two FA molecules and identify hundreds of FA cross-links by XLMS in vitro and in situ.
- Tamar Tayri-Wilk
- , Moriya Slavin
- & Nir Kalisman
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Article
| Open AccessTraceless native chemical ligation of lipid-modified peptide surfactants by mixed micelle formation
Sequestration of reactants in lipid vesicles is a strategy prevalent in biological systems to raise the rate and specificity of chemical reactions. Here, the authors show that micelle-assisted reactions facilitate native chemical ligation between a peptide-thioester and a Cys-peptide modified by a lipid-like moiety.
- Shuaijiang Jin
- , Roberto J. Brea
- & Neal K. Devaraj
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Article
| Open AccessConstruction of a web-based nanomaterial database by big data curation and modeling friendly nanostructure annotations
The low curation of existing nanomaterials’s databases is limiting their application in modeling studies. Here the authors report a publicly available nanomaterial database that contains annotated nanostructures of diverse nanomaterials immediately available for modeling research studies.
- Xiliang Yan
- , Alexander Sedykh
- & Hao Zhu
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Article
| Open AccessChemical modification of proteins by insertion of synthetic peptides using tandem protein trans-splicing
Chemical modification of proteins can be used to decipher function or use that function for therapeutic purposes. Here, the authors insert synthetic peptides via tandem protein trans-splicing to add post-translational modifications or non-canonical amino acids.
- K. K. Khoo
- , I. Galleano
- & S. A. Pless
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Article
| Open AccessA pocket-escaping design to prevent the common interference with near-infrared fluorescent probes in vivo
Near-infrared fluorescent probes hold great potential for biomedical imaging but most bind to albumin, generating unspecific fluorescence. Here the authors identify the acceptor (A) group as responsible and design a new A group that avoids capture by albumin, and apply it to imaging liver fibrosis in vivo.
- Panfei Xing
- , Yiming Niu
- & Chunming Wang
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Article
| Open AccessLipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection
Granadaene, produced by Group B Streptococcus (GBS), is a long polyene lipid involved in cellular toxicity and hemolytic activity. Here, the authors synthesize and characterize granadaene-like compounds and show that a non-toxic analog diminishes GBS infection in mice when incorporated into a vaccine formulation.
- Blair Armistead
- , Pilar Herrero-Foncubierta
- & Lakshmi Rajagopal
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Article
| Open AccessAptamer-based optical manipulation of protein subcellular localization in cells
Optogenetic manipulation of protein localisation in cells involves the creation of fusions that can influence activity. Here the authors develop a near-infrared light-responsive aptamer-based system to regulate the nuclear-cytoplasmic shuttling of NF-κB subunit RelA.
- Sitao Xie
- , Yulin Du
- & Weihong Tan
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Article
| Open AccessDNA-based artificial molecular signaling system that mimics basic elements of reception and response
Cells communicate with the outside world to maintain homeostasis. Here the authors design a synthetic biology DNA-based signalling system AMSsys that responds to the presence of ATP.
- Ruizi Peng
- , Liujun Xu
- & Weihong Tan
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Article
| Open AccessSuper-resolution microscopy compatible fluorescent probes reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics
Glucagon-like peptide-1 receptor is an important regulator of appetite and glucose homeostasis. Here the authors describe super-resolution microscopy and in vivo imaging compatible fluorescent probes, which reveal endogenous glucagon-like peptide-1 receptor distribution and dynamics in islets and brain.
- Julia Ast
- , Anastasia Arvaniti
- & David J. Hodson
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Article
| Open AccessImage-guided neural activity manipulation with a paramagnetic drug
Targeted manipulations of neural activity in the living brain remain a significant challenge. In this study the authors introduce a paramagnetic analog of the drug muscimol that enables targeted neural inactivation to be performed with feedback from magnetic resonance imaging
- Sarah Bricault
- , Ali Barandov
- & Alan Jasanoff
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Article
| Open AccessDiscovery of a chemical probe for PRDM9
PRDM9 is a PR domain containing histone methyl transferase which expression is normally restricted to the germline that has also been linked to a number of somatic cancers. Here the authors describe the identification of a small molecule that selectivity inhibits the methyltransferase activity of PRDM9 in biochemical and cellular assays
- Abdellah Allali-Hassani
- , Magdalena M. Szewczyk
- & Masoud Vedadi
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Article
| Open AccessNanosecond photochemically promoted click chemistry for enhanced neuropeptide visualization and rapid protein labeling
Mass spectrometry-based quantitative proteomics aim to identify and quantify proteins from complex biological samples. Here, the authors developed a method for simultaneous high-throughput protein labelling and on-demand matrix removal within nanoseconds.
- Gongyu Li
- , Fengfei Ma
- & Lingjun Li
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Article
| Open AccessEngineering selective competitors for the discrimination of highly conserved protein-protein interaction modules
Developing inhibitors that target specific protein-protein interactions (PPIs) is challenging. Here, the authors show that target selectivity and PPI blocking can be achieved simultaneously with PPI inhibitors that contain two functional modules, and create a paralog-selective PSD-95 inhibitor as proof-of-concept.
- Charlotte Rimbault
- , Kashyap Maruthi
- & Matthieu Sainlos
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Article
| Open AccessMonitoring cytosolic H2O2 fluctuations arising from altered plasma membrane gradients or from mitochondrial activity
Reliable methods of measuring intracellular H2O2 fluctuations are necessary to advance redox biology. Here the authors design a H2O2 sensor based on the fission yeast peroxiredoxin Tpx1 to sense nanomolar fluctuations of intracellular H2O2 in response to genetic and environmental perturbations.
- Mercè Carmona
- , Laura de Cubas
- & Elena Hidalgo