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Nature Chemical Biology
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Nature Chemical Biology is a monthly multidisciplinary journal providing an international forum for the timely publication of significant new research at the interface between chemistry and biology. Published in hard copy and online, Nature Chemical Biology is a medium for rapid publication and for the exchange of ideas between scientists in both the chemical and the life sciences.
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In This Issue
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Keeping chemistry in the equation
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The integration of cell and chemical biology in protein folding
Eukaryotic cells are specialized, interdependent functional units of complex tissues that are composed of metabolically integrated systems defined by chemically distinct organelles that operate as reaction vessels. It is now clear that the small-molecule and polymer-based composition of these organelles plays a crucial role in generating and maintaining protein folds and functions through the systems chemistry of the local environments.
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Fishing and frogging for anti-angiogenic drugs
There is a growing medical need for additional anti-angiogenic drugs. A new model of regenerative angiogenesis in the fin of adult zebrafish promises to accelerate discovery of genes and drugs related to angiogenesis.
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Metalloproteases see the light
Small-molecule probes that chemically tag targets by virtue of their enzymatic activities offer a means to focus system-wide experiments and provide functional information for entire families of proteins. Recent advances in the design and application of light-activated probes that target metalloproteases have created the opportunity to study this medically important family of enzymes in unprecedented detail.
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A library of RNA bridges
Translation starts with the assembly of the ribosome from its subunits, which requires the formation of intersubunit bridges. A combinatorial mutagenesis approach has now identified a number of the 16S rRNA residues involved in intersubunit bridging that are functionally important for the ribosome.
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Remarkable structural variation within fatty acid megasynthases
The crystal structures of two chain-building megasynthases, the fatty acid synthases of mammals and fungi, have recently been reported. Although both are composed of modules derived from the discrete enzymes that catalyze bacterial fatty acid synthesis, the two synthases have dramatically different architectures.
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Redox sensing and histidine oxidation: no longer PerR-fect strangers
Oxidation of cysteine residues is a well-described means of sensing oxidative stress. Analysis of a bacterial transcriptional repressor protein indicates that metal-catalyzed oxidation of histidine residues can provide oxidative stress control in a cysteine-independent fashion.
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Research Highlights
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Sweet spots in functional glycomics
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Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate ?-synuclein fibrilization
Oxidative stress, inflammation and ?-synuclein overexpression confer risk for development of ?-synucleinopathies?neurodegenerative diseases that include Parkinson disease and Lewy body dementia. Dopaminergic neurons undergo degeneration in these diseases and are particularly susceptible to oxidative stress because dopamine metabolism itself creates reactive oxygen species. Intraneuronal deposition of ?-synuclein as amyloid fibrils or Lewy bodies is the hallmark of these diseases. Herein, we demonstrate that concentrations of oxidative cholesterol metabolites derived from reactive oxygen species are elevated in the cortices of individuals with Lewy body dementia relative to those of age-matched controls, and we show that these metabolites accelerate ?-synuclein aggregation in vitro. The increase in the production of these cytotoxic cholesterol metabolites is also observed in a dopaminergic cell line that overexpresses ?-synuclein. By extension, these data lead to the hypothesis that oxidative stress produces cholesterol aldehydes that enable ?-synuclein aggregation, leading to a pathologic cycle.
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Functional epitopes at the ribosome subunit interface
The ribosome is a 2.5-MDa molecular machine that synthesizes cellular proteins encoded in mRNAs. The 30S and 50S subunits of the ribosome associate through structurally defined intersubunit bridges burying 6,000 Å2, 80% of which is buried in conserved RNA-RNA interactions. Intersubunit bridges bind translation factors, may coordinate peptide bond formation and translocation and may be actively remodeled in the post-termination complex, but the functional importance of numerous 30S bridge nucleotides had been unknown. We carried out large-scale combinatorial mutagenesis and in vivo selections on 30S nucleotides that form RNA-RNA intersubunit bridges in the Escherichia coli ribosome. We determined the covariation and functional importance of bridge nucleotides, allowing comparison of the structural interface and phylogenetic data to the functional epitope. Our results reveal how information for ribosome function is partitioned across bridges, and suggest a subset of nucleotides that may have measurable effects on individual steps of the translational cycle.
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Atomic resolution crystallography reveals how changes in pH shape the protein microenvironment
Hydrogen atoms are a vital component of enzyme structure and function. In recent years, atomic resolution crystallography (?1.2 Å) has been successfully used to investigate the role of the hydrogen atom in enzymatic catalysis. Here, atomic resolution crystallography was used to study the effect of pH on cholesterol oxidase from Streptomyces sp., a flavoenzyme oxidoreductase. Crystallographic observations of the anionic oxidized flavin cofactor at basic pH are consistent with the UV-visible absorption profile of the enzyme and readily explain the reversible pH-dependent loss of oxidation activity. Furthermore, a hydrogen atom, positioned at an unusually short distance from the main chain carbonyl oxygen of Met122 at high pH, was observed, suggesting a previously unknown mechanism of cofactor stabilization. This study shows how a redox active site responds to changes in the enzyme's environment and how these changes are able to influence the mechanism of enzymatic catalysis.
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Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish
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Proteomic profiling of metalloprotease activities with cocktails of active-site probes
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