Nature Chemical Biology

Simultaneous quantification of protein order and disorder ()
Nuclear magnetic resonance spectroscopy is transforming our views of proteins by revealing how their structures and dynamics are closely intertwined to underlie their functions and interactions. Compelling representations of proteins as statistical ensembles are uncovering the presence and biological relevance of conformationally heterogeneous states, thus gradually making it possible to go beyond the dichotomy between order and disorder through more quantitative descriptions that span the continuum between them.
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Development: Marking the transition ()

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Bioconjugation: Methionine's time to shine ()

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Drug discovery: Uncoupling coupled transport ()

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Imaging: Luciferase matchmaker ()

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Fatty acid synthases: Re-engineering biofactories ()
Systematically modifying biological assembly lines for the synthesis of novel products remains a challenge. Structural insights and computational modeling have now paved the way for efficient redesigns of giant fatty acid synthases.
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Chromatin biology: Breaking into the PRC2 cage ()
New small-molecule inhibitors of the histone methyltransferase PRC2 interfere with the allosteric activation of enzymatic activity. These compounds are effective against PRC2-dependent tumors that are resistant to catalytic inhibitors and provide important new tools for altering chromatin regulation.
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Protein folding: Illuminating chaperone activity ()
Pharmacological chaperones are small drugs that stabilize a protein's fold and are being developed to treat diseases arising from protein misfolding. A mathematical framework to model their activity in cells enables insight into their mechanism and capacity to rescue protein foldedness.
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Signaling: Spatial regulation of axonal cAMP ()
In early-stage developing neurons, the cAMP–PKA (protein kinase A) signaling pathway is strongly inhibited. This negative control is later removed, unleashing cAMP–PKA signaling, particularly in distal axonal parts, thus allowing for axonal growth.
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Versatile modes of cellular regulation via cyclic dinucleotides ()

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Expanding the product portfolio of fungal type I fatty acid synthases ()
Fungal type I fatty acid synthases (FASs) are mega-enzymes with two separated, identical compartments, in which the acyl carrier protein (ACP) domains shuttle substrates to catalytically active sites embedded in the chamber wall. We devised synthetic FASs by integrating heterologous enzymes into the reaction chambers and demonstrated their capability to convert acyl-ACP or acyl-CoA from canonical fatty acid biosynthesis to short/medium-chain fatty acids and methyl ketones.
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Engineering fatty acid synthases for directed polyketide production ()
In this study, we engineered fatty acid synthases (FAS) for the biosynthesis of short-chain fatty acids and polyketides, guided by a combined in vitro and in silico approach. Along with exploring the synthetic capability of FAS, we aim to build a foundation for efficient protein engineering, with the specific goal of harnessing evolutionarily related megadalton-scale polyketide synthases (PKS) for the tailored production of bioactive natural compounds.
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Structure and specificity of a permissive bacterial C-prenyltransferase ()
This study highlights the biochemical and structural characterization of the L-tryptophan C6 C-prenyltransferase (C-PT) PriB from Streptomyces sp. RM-5-8. PriB was found to be uniquely permissive to a diverse array of prenyl donors and acceptors including daptomycin. Two additional PTs also produced novel prenylated daptomycins with improved antibacterial activities over the parent drug.
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Ligand-promoted protein folding by biased kinetic partitioning ()
Protein folding in cells occurs in the presence of high concentrations of endogenous binding partners, and exogenous binding partners have been exploited as pharmacological chaperones. A combined mathematical modeling and experimental approach shows that a ligand improves the folding of a destabilized protein by biasing the kinetic partitioning between folding and alternative fates (aggregation or degradation). Computationally predicted inhibition of test protein aggregation and degradation as a function of ligand concentration are validated by experiments in two disparate cellular systems.
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HTS-compatible FRET-based conformational sensors clarify membrane receptor activation ()

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An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED ()

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The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex ()

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In vitro reconstitution demonstrates the cell wall ligase activity of LCP proteins ()

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A water-mediated allosteric network governs activation of Aurora kinase A ()

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A tight tunable range for Ni(II) sensing and buffering in cells ()

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Selective in vivo metabolic cell-labeling-mediated cancer targeting ()

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AKAP-mediated feedback control of cAMP gradients in developing hippocampal neurons ()

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Evolution of a split RNA polymerase as a versatile biosensor platform ()

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The GlcN6P cofactor plays multiple catalytic roles in the glmS ribozyme ()

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An orthogonalized platform for genetic code expansion in both bacteria and eukaryotes ()

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