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| Open AccessACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury
Endogenous ACE2 is a receptor for SARS-CoV-2 and a recombinant soluble ACE2 protein can inhibit SARS-CoV-2 infection acting as a decoy. Here the authors show that B38-CAP, an ACE2-like enzyme but not a decoy for the virus, is protective against SARS-CoV-2-induced lung injury in animal models.
- Tomokazu Yamaguchi
- , Midori Hoshizaki
- & Keiji Kuba
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Article
| Open AccessAntibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus
Antibiotic resistance in Staphylococcus aureus is associated with reduced neutrophil recruitment. Here, Payne et al. link formylated peptides, which act as chemoattractants for neutrophils, with the antibiotic vancomycin and show that these hybrid compounds improve clearance of S. aureus by neutrophils.
- Jennifer A. E. Payne
- , Julien Tailhades
- & Max J. Cryle
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Article
| Open AccessProtein identification by nanopore peptide profiling
Peptide mass fingerprinting is a traditional approach for protein identification by mass spectrometry. Here, the authors provide evidence that peptide mass fingerprinting is also feasible using FraC nanopores, demonstrating protein identification based on nanopore measurements of digested peptides.
- Florian Leonardus Rudolfus Lucas
- , Roderick Corstiaan Abraham Versloot
- & Giovanni Maglia
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Article
| Open AccessConformational rearrangements enable iterative backbone N-methylation in RiPP biosynthesis
Borosins are ribosomally encoded and posttranslationally modified peptide (RiPP) natural products featuring amide-backbone α-N-methylation. Here, the authors report the discovery and characterization of type IV borosin ‘split’ pathways encoding distinct, separate α-N-methyltransferases and precursor peptide substrates.
- Fredarla S. Miller
- , Kathryn K. Crone
- & Michael F. Freeman
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Article
| Open AccessFacile access to C-glycosyl amino acids and peptides via Ni-catalyzed reductive hydroglycosylation of alkynes
C-Glycosyl peptides/proteins are metabolically stable mimics of the native glycopeptides/proteins of great therapeutic potential, but their chemical synthesis is challenging. Here, the authors report a protocol for the synthesis of vinyl C-glycosyl amino acids and peptides, via a Ni-catalyzed reductive hydroglycosylation reaction of alkyne derivatives of amino acids and peptides with glycosyl bromides.
- Yan-Hua Liu
- , Yu-Nong Xia
- & Biao Yu
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Article
| Open AccessRapid discovery of self-assembling peptides with one-bead one-compound peptide library
Self-assembling peptides have a range of potential applications but developing self-assembling sequences can be challenging. Here, the authors report on a one-bead one-compound combinatorial library where fluorescence is used to detect the potential for self-assembly and identified candidates are evaluated.
- Pei-Pei Yang
- , Yi-Jing Li
- & Kit S. Lam
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Article
| Open Accessα-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity
α-Synuclein (αS) aggregation is a driver of several neurodegenerative disorders. Here, the authors identify a class of peptides that bind toxic αS oligomers and amyloid fibrils but not monomeric functional protein, and prevent further αS aggregation and associated cell damage.
- Jaime Santos
- , Pablo Gracia
- & Salvador Ventura
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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 AccessAnchor extension: a structure-guided approach to design cyclic peptides targeting enzyme active sites
Cyclic peptides are of particular interest due to their pharmacological properties, but their design for binding to a target protein is challenging. Here, the authors present a computational “anchor extension” methodology for de novo design of cyclic peptides that bind to the target protein with high affinity, and validate the approach by developing cyclic peptides that inhibit histone deacetylases 2 and 6.
- Parisa Hosseinzadeh
- , Paris R. Watson
- & David Baker
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Article
| Open AccessAutomated annotation and visualisation of high-resolution spatial proteomic mass spectrometry imaging data using HIT-MAP
MALDI-mass spectrometry imaging (MSI) can reveal the distribution of proteins in tissues but tools for protein identification and annotation are sparse. Here, the authors develop an open-source bioinformatic workflow for false discovery rate-controlled protein annotation and spatial mapping from MALDI-MSI data.
- G. Guo
- , M. Papanicolaou
- & A. C. Grey
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Article
| Open AccessA minimalistic cyclic ice-binding peptide from phage display
Developing molecules that emulate the properties of naturally occurring ice-binding proteins (IBPs) is a daunting challenge. Here, the authors demonstrate the use of phage display for the identification of short peptide mimics of IBPs, which resulted in the identification of a cyclic ice-binding peptide containing just 14 amino acids.
- Corey A. Stevens
- , Fabienne Bachtiger
- & Harm-Anton Klok
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Article
| Open AccessModification of N-terminal α-amine of proteins via biomimetic ortho-quinone-mediated oxidation
Methods for selective modification of the N-terminus of proteins are of high interest, but mostly require specific amino acid residues. Here, the authors report a selective and fast method for N-terminal modification of proteins based on quinone-mediated oxidation of the alpha-amine to aldehyde or ketone, and apply it to diverse proteins.
- Siyao Wang
- , Qingqing Zhou
- & Ping Wang
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Article
| Open AccessHierarchized phosphotarget binding by the seven human 14-3-3 isoforms
14-3-3 proteins recognize phosphorylated motifs within numerous protein partners. Here, the authors characterize the binding of all human 14-3-3 isoforms to four E6 oncoproteins, and identify a fixed order of 14-3-3 binding affinities that is conserved in 14-3-3:phosphoprotein interactions across the proteome.
- Gergo Gogl
- , Kristina V. Tugaeva
- & Nikolai N. Sluchanko
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Article
| Open AccessLasso-grafting of macrocyclic peptide pharmacophores yields multi-functional proteins
RaPID (Random non-standard Peptides Integrated Discovery) enables discovery of small macrocyclic peptides binding desired targets. Here, the authors propose lasso-grafting: the RaPID-derived peptides are implanted onto diverse proteins and maintain both the binding properties of the cyclic peptide and the host protein function.
- Emiko Mihara
- , Satoshi Watanabe
- & Junichi Takagi
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Article
| Open AccessAlt-RPL36 downregulates the PI3K-AKT-mTOR signaling pathway by interacting with TMEM24
Many alternative ORFs are co-encoded with characterized proteins, but their function is often not understood. Here, the authors discover that ribosomal protein L36 is co-encoded with alternative protein, which they identify as an upstream regulator of PI3K-AKT-mTOR signaling.
- Xiongwen Cao
- , Alexandra Khitun
- & Sarah A. Slavoff
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Article
| Open AccessMOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis
Exercise has beneficial effects on metabolism and overall physiologic fitness in aged organisms. Here the authors show that MOTS-c is a mitochondrial-encoded exercise-induced peptide that regulates skeletal muscle metabolism and improves healthspan of older mice.
- Joseph C. Reynolds
- , Rochelle W. Lai
- & Changhan Lee
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Article
| Open AccessA metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia
Apelin and AVP have opposing effects water balance in humans and rodents. Here, the authors report that a metabolically stable apelin-17 analog, by acting at the kidney level, reduces AVP-induced antidiuresis and improves hyponatremia in rodents, demonstrating a potential approach for treating water metabolism disorders.
- Adrien Flahault
- , Pierre-Emmanuel Girault-Sotias
- & Catherine Llorens-Cortes
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Article
| Open AccessThioesterase-mediated side chain transesterification generates potent Gq signaling inhibitor FR900359
FR900359 (FR) is a Gq protein inhibitor depsipeptide isolated from an uncultivable plant endosymbiont and synthesized by non-ribosomal peptide synthetases. Here, the authors discover a cultivable bacterial FR producer and show that FrsA thioesterase domain catalyses intermolecular transesterification of the FR side chain to the depsipeptide core during biosynthesis, improving Gq inhibition properties.
- Cornelia Hermes
- , René Richarz
- & Max Crüsemann
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Article
| Open AccessHydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases
Current histone microarrays cannot be used to directly study the transient interactions of histone deacetylases (HDACs). Here, the authors show that hydroxamic acid-modified microarrays can capture HDACs, provide insights into their substrate specificity, and serve to develop peptide inhibitors.
- Carlos Moreno-Yruela
- , Michael Bæk
- & Christian A. Olsen
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Article
| Open AccessDesigned CXCR4 mimic acts as a soluble chemokine receptor that blocks atherogenic inflammation by agonist-specific targeting
The development of specific anti-cytokine/chemokine therapeutic strategies for atherosclerotic disease is challenging. Here, the authors have designed a peptide-based ectodomain mimic of the chemokine receptor CXCR4 that selectively targets MIF but not CXCL12 and blocks experimental atherosclerosis in vivo.
- Christos Kontos
- , Omar El Bounkari
- & Jürgen Bernhagen
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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 AccessA protein tertiary structure mimetic modulator of the Hippo signalling pathway
Targeting the interaction between transcription factor TEAD and its co-repressor VGL4 is an attractive strategy to chemically modulate Hippo signaling. Here, the authors develop a proteomimetic with stabilized tertiary structure that inhibits the TEAD:VGL4 interaction in vitro and in cells.
- Hélène Adihou
- , Ranganath Gopalakrishnan
- & Herbert Waldmann
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Article
| Open AccessOxepinamide F biosynthesis involves enzymatic d-aminoacyl epimerization, 3H-oxepin formation, and hydroxylation induced double bond migration
Oxepinamides are a class of fungal oxepins with biological activities. Here, the authors elucidate the biosynthetic pathway of oxepinamide F from Aspergillus ustus and show that it involves enyme-catalysed oxepin ring formation, hydroxylation-induced double bond migration, epimerization and methylation.
- Liujuan Zheng
- , Haowen Wang
- & Shu-Ming Li
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Article
| Open AccessDiscovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library
The strong hemolytic activity and mammalian cytotoxicity of gramicidin A, a peptide antibiotic, has hindered its non-topical clinical application. Here, the authors report a high-throughput strategy for the discovery of gramicidin A analogues with altered biological activity profiles.
- Yuri Takada
- , Hiroaki Itoh
- & Masayuki Inoue
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Article
| Open AccessRibosome-mediated polymerization of long chain carbon and cyclic amino acids into peptides in vitro
Backbone extended monomers are poorly compatible with the natural ribosomes, impeding their polymerization into polypeptides. Here the authors design non-canonical amino acid analogs with cyclic structures or extended carbon chains and used an engineered ribosome to improve tRNA-charging and incorporation into peptides.
- Joongoo Lee
- , Kevin J. Schwarz
- & Michael C. Jewett
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Article
| Open AccessIdentification of modified peptides using localization-aware open search
Mass spectrometry-based proteomics is the method of choice for the global mapping of post-translational modifications, but matching and scoring peaks with unknown masses remains challenging. Here, the authors present a refined open search strategy to score all peaks with higher sensitivity and accuracy.
- Fengchao Yu
- , Guo Ci Teo
- & Alexey I. Nesvizhskii
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Article
| Open AccessDissecting the sequence determinants for dephosphorylation by the catalytic subunits of phosphatases PP1 and PP2A
The substrate specificity of phosphoprotein phosphatases PP1 and PP2A depends on their catalytic and regulatory subunits. Using proteomics approaches, the authors here provide insights into the sequence specificity of the catalytic subunits and their distinct contributions to PP1 and PP2A selectivity.
- Bernhard Hoermann
- , Thomas Kokot
- & Maja Köhn
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Article
| Open AccessCharacterization of an alternative BAK-binding site for BH3 peptides
Mitochondrial apoptosis is controlled by BCL2 family proteins, and the BH3-only proteins often act as sensors that transmit apoptotic signals. Here the authors show how the BH3-only proteins BMF and HRK can directly activate the BCL2 protein BAK and interact with BAK through an alternative binding groove.
- Kaiqin Ye
- , Wei X. Meng
- & Haiming Dai
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Article
| Open AccessUltra-large chemical libraries for the discovery of high-affinity peptide binders
Synthetic peptide libraries can access broad chemical space, but generally examine only ~ 106 compounds. Here, the authors show that in-solution affinity selection, interfaced with nLC-MS/MS sequencing, can identify binders from fully randomized synthetic libraries of 108 members.
- Anthony J. Quartararo
- , Zachary P. Gates
- & Bradley L. Pentelute
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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 AccessMultiplexed relative and absolute quantitative immunopeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition
Immunopeptidomics allows identifying the cellular repertoire of MHC-bound peptides, but quantifying them remains challenging. Here, the authors present a method to efficiently generate internal peptide MHC standards and calibration curves, facilitating relative and absolute quantitative immunopeptidomics.
- Lauren E. Stopfer
- , Joshua M. Mesfin
- & Forest M. White
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Article
| Open AccessTrefoil factors share a lectin activity that defines their role in mucus
Trefoil factors (TFFs) protect the mucosa and have various reported binding activities, but whether they share a common interaction mechanism has remained unclear. Here, the authors provide structural and biochemical evidence that all three human TFFs are divalent lectins that recognise the same disaccharide.
- Michael A. Järvå
- , James P. Lingford
- & Ethan D. Goddard-Borger
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Article
| Open AccessSpider venom-derived peptide induces hyperalgesia in Nav1.7 knockout mice by activating Nav1.9 channels
Loss of function of Nav1.7 leads to congenital insensitivity to pain in humans. Here the authors found that activation of Nav1.9 can restore nociception in Nav1.7 knockout mice, revealed by a venom-derived peptide as a probe.
- Xi Zhou
- , Tingbin Ma
- & Zhonghua Liu
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Article
| Open AccessNeuromedin U signaling regulates retrieval of learned salt avoidance in a C. elegans gustatory circuit
Learning and memory are regulated by neuropeptides. Here, the authors show that the neuropeptide CAPA-1 and its receptor NMUR-1 are required to retrieve learned salt avoidance in C. elegans. CAPA-1/NMUR-1 activation in AFD sensory neurons modulates locomotor programs to express learned avoidance.
- Jan Watteyne
- , Katleen Peymen
- & Isabel Beets
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Article
| Open AccessImproved GPCR ligands from nanobody tethering
Antibodies conjugated to bioactive compounds can allow targeted delivery of therapeutics. Here the authors present a strategy for fusing nanobodies to suboptimal GPCR peptide ligands to potently and selectively activate receptors.
- Ross W. Cheloha
- , Fabian A. Fischer
- & Hidde L. Ploegh
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Article
| Open AccessModulation of virus-induced NF-κB signaling by NEMO coiled coil mimics
NF-κB signalling involves the scaffold protein NEMO, which can be bound by the oncoprotein vFLIP to promote cell survival and oncogenic transformation. Here the authors rationally engineer a tertiary protein mimic of NEMO to disrupt the vFLIP-NEMO interaction to induce cell death.
- Jouliana Sadek
- , Michael G. Wuo
- & Paramjit S. Arora
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Article
| Open AccessA bifunctional asparaginyl endopeptidase efficiently catalyzes both cleavage and cyclization of cyclic trypsin inhibitors
Asparaginyl endopeptidases (AEPs) catalyze the cyclization step during the biosynthesis of cyclic peptides in plants. Here, the authors report a recombinantly produced AEP that catalyzes the backbone cyclization of a linear cyclotide precursor and an engineered analog with high efficiency and in a pH-dependent manner.
- Junqiao Du
- , Kuok Yap
- & David J. Craik
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Article
| Open AccessAn amber obligate active site-directed ligand evolution technique for phage display
Most epigenetic regulator inhibitors target tunnels of active sites, rather than the peptide binding groove, leading to concerns with low selectivity. Here the authors use an amber obligate phage library to rapidly identify isoform-selective inhibitors of SIRT2.
- Jeffery M. Tharp
- , J. Trae Hampton
- & Wenshe Ray Liu
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Article
| Open AccessIntegrated proteogenomic deep sequencing and analytics accurately identify non-canonical peptides in tumor immunopeptidomes
Non-canonical HLA-bound peptides from presumed non-coding regions are potential targets for cancer immunotherapy, but their discovery remains challenging. Here, the authors integrate exome sequencing, transcriptomics, ribosome profiling, and immunopeptidomics to identify tumor-specific non-canonical HLA-bound peptides.
- Chloe Chong
- , Markus Müller
- & Michal Bassani-Sternberg
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Article
| Open AccessTargeting the tumor vasculature with engineered cystine-knot miniproteins
Cystine-knot miniprotein are small, highly stable, disulfide-rich peptides with increasing potential as drugs and tumor imaging agents. Here the authors develop cystine-knot miniproteins targeting the vascular tumor marker EDB, and use them as probes for in vivo tumor vasculature imaging.
- Bonny Gaby Lui
- , Nadja Salomon
- & Ugur Sahin
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Article
| Open AccessPBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth
Acetylation of p53 is critical for its transcriptional activity and its tumour suppressive function. Here, the authors show that PBRM1 is a reader protein for p53′s C-terminal domain acetylation on lysine 382 through its bromodomain 4 and that mutations in this domain leads to compromised tumour suppressive function and renal tumour growth.
- Weijia Cai
- , Liya Su
- & Haifeng Yang
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Article
| Open AccessMolecular basis for chirality-regulated Aβ self-assembly and receptor recognition revealed by ion mobility-mass spectrometry
Chiral inversion of amino acids is thought to modulate the structure and function of amyloid beta (Aβ) but these processes are poorly understood. Here, the authors develop an ion mobility-mass spectrometry based approach to study chirality-regulated structural features of Aβ fragments and their influence on receptor recognition.
- Gongyu Li
- , Kellen DeLaney
- & Lingjun Li
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Article
| Open AccessA tumour-selective cascade activatable self-detained system for drug delivery and cancer imaging
The activation of drugs within cellular systems may provide targeted therapies for cancer. Here, the authors make a drug delivery system that is activated within the cell and exploits XIAP expression to cleave a linker region, resulting in the self-assembly of the system and drug release within cancer cells.
- Hong-Wei An
- , Li-Li Li
- & Yuliang Zhao
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Article
| Open AccessSelf-assembling peptides imaged by correlated liquid cell transmission electron microscopy and MALDI-imaging mass spectrometry
Peptide self-assembly into fibres is prevalent in nature in normal tissue and in degenerative diseases. Here, the authors report on the coupling of liquid cell TEM with MALDI-imaging mass spectrometry to study processes of peptide fibre formation, in solution, in real time with nanoscale resolution.
- Mollie A. Touve
- , Andrea S. Carlini
- & Nathan C. Gianneschi
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Article
| Open AccessStructure of ribosome-bound azole-modified peptide phazolicin rationalizes its species-specific mode of bacterial translation inhibition
The authors report the identification of phazolicin (PHZ) - a prokaryotic translation inhibitory peptide - and its structure in complex with the E. coli ribosome, delineating PHZ’s mode of action and suggesting a basis for its bacterial species-specific activity.
- Dmitrii Y. Travin
- , Zoe L. Watson
- & Konstantin Severinov
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Article
| Open AccessPrebiotic condensation through wet–dry cycling regulated by deliquescence
Wet–dry cycling is regarded as a possible driving force of condensation reactions under prebiotic conditions. Here, the authors propose that water uptake by deliquescent minerals could have facilitated the wet phase and simulate this scenario using the oligomerization of glycine as a model reaction.
- Thomas D. Campbell
- , Rio Febrian
- & Paul J. Bracher
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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 AccessEnzymatic biosynthesis and immobilization of polyprotein verified at the single-molecule level
Existing methods for protein polymer engineering suffer from low efficiency especially for synthesis large size polyproteins. Here, Deng et al. construct homo-polymer and co-polymer up to decamer by stepwise ligation and cleavage validated by atomic force microscopy-based single-molecule force spectroscopy.
- Yibing Deng
- , Tao Wu
- & Peng Zheng
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Article
| Open AccessStructural insights into substrate recognition by the SOCS2 E3 ubiquitin ligase
The suppressor of cytokine signaling 2 (SOCS2) is a component of the Cullin5 E3 ubiquitin ligase complex. Here the authors provide insights into substrate recognition and specificity of SOCS2 by determining the crystal structures of the SOCS2-ElonginB-ElonginC in complex with phosphorylated peptides from two of its substrates the growth hormone receptor and erythropoietin receptor.
- Wei-Wei Kung
- , Sarath Ramachandran
- & Alessio Ciulli