Simultaneous quantification of protein order and disorder pp339 - 342 Pietro Sormanni, Damiano Piovesan, Gabriella T Heller, Massimiliano Bonomi, Predrag Kukic et al. doi:10.1038/nchembio.2331 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.
Fatty acid synthases: Re-engineering biofactories pp344 - 345 Timm Maier doi:10.1038/nchembio.2338 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.
Chromatin biology: Breaking into the PRC2 cage pp345 - 346 Daniel Holoch and Raphael Margueron doi:10.1038/nchembio.2313 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.
Protein folding: Illuminating chaperone activity pp346 - 347 Danny M Hatters doi:10.1038/nchembio.2332 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.
Signaling: Spatial regulation of axonal cAMP pp348 - 349 Pierre Vincent and Liliana R Castro doi:10.1038/nchembio.2339 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.
Versatile modes of cellular regulation via cyclic dinucleotides pp350 - 359 Petya Violinova Krasteva and Holger Sondermann doi:10.1038/nchembio.2337 A review of the roles of cyclic dinucleotides (CDNs) in signaling systems including transcription, ion transport, bacterial secretion and eukaryotic immune responses, highlighting the diverse binding modes of CDNs by target proteins and functional insights gained from structural studies.
Integration of heterologous enzymes into the reaction chambers of fungal fatty acid synthases (FASs) demonstrates the capacity of these megaenzymes for engineered production of short- and medium-chain fatty acids and methyl ketones.
Discovery and characterization of an unusually permissive C-prenyltransferase provides a biocatalytic route for generating novel prenylated compounds, including daptomycin derivatives with increased potency. Chemical compounds
Pharmacological chaperones improve folding of destabilized Escherichia coli dihydrofolate reductase (DHFR) and human disease-linked α-galactosidase A (α-GAL) by biasing the kinetic partitioning between folding, aggregation, and degradation. Chaperoning spares DHFR from aggregation and α-GAL from degradation.
Optimizing the signal-to-noise ratio in time-resolved FRET through generation of agonist-responsive cell-surface receptor biosensors, including GABAB receptors and EGFR, which are useful for monitoring conformational changes associated with receptor activation. Chemical compounds
Reconstitution experiments using substrates prepared by chemoenzymatic synthesis demonstrate that three LCP family proteins catalyze the ligation of wall teichoic acids to peptidoglycan in the biosynthesis of the Staphylococcus aureus cell wall.
Spectroscopic studies of allosteric activation of Aurora A kinase using a site-specific infrared probe combined with FRET analysis and molecular dynamics simulations reveals a water-mediated hydrogen bond network in the active site that regulates Aurora A activity.
Metabolic labeling of the cell surface with a caged azide sugar enabled cleavage-mediated activation by enzymes overexpressed in cancer cells, allowing enhanced targeted delivery of a doxorubicin conjugate through copper-free click chemistry. Chemical compounds
A gradient of cAMP in developing hippocampal neurons that is important for axon elongation is shaped by spatial differences in phosphodiesterase localization and is maintained by AKAP-anchored PKA, as revealed by using FRET-based biosensors.
Design of a proximity-dependent split RNA polymerase system and its optimization by phage-assisted continuous evolution (PACE) enabled the development of a family of activity-dependent split RNA polymerase biosensors regulated by small molecules or light.
Experimental work and computational modeling together reveal a suite of catalytic roles of the GlcN6P cofactor in the glmS ribozyme, including activation of the nucleophile, electrostatic stabilization, and alignment of the active site.
In Escherichia coli, replacement of the endogenous tryptophanyl-tRNA synthetase-tRNA pair with its counterpart from Saccharomyces cerevisiae liberates the bacterial counterpart for directed evolution to incorporate unnatural amino acids in both E. coli and eukaryotes. Chemical compounds
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