Top 5 Biorxiv Papers Today in Biochemistry


2.009 Mikeys
#1. Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase
Ricky Cain, Ramya Salimaraj, Avinash S Punekar, Dom Bellini, Colin W.G. Fishwisk, Lloyd Czapleski, David J Scott, Gemma Harris, Christopher G Dowson, Adrian J Lloyd, David I Roper
Aminoacyl-tRNA synthetases are ubiquitous and essential enzymes for protein synthesis and also a variety of other metabolic processes, especially in bacterial species. Bacterial aminoacyl-tRNA synthetases represent attractive and validated targets for antimicrobial drug discovery if issues of prokaryotic versus eukaryotic selectivity and antibiotic resistance generation can be addressed. We have determined high resolution X-ray crystal structures of the Escherichia coli and Staphylococcus aureus seryl-tRNA synthetases in complex with aminoacyl adenylate analogues and applied a structure-based drug discovery approach to explore and identify a series of small molecule inhibitors that selectively inhibit bacterial seryl-tRNA synthetases with greater than two orders of magnitude compared to their human homologue, demonstrating a route to selective chemical inhibition of these bacterial targets.
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biorxivpreprint: Structure-guided enhancement of selectivity of chemical probe inhibitors targeting bacterial seryl-tRNA synthetase https://t.co/OKI4LWDakG #bioRxiv
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Authors: 11
Total Words: 6957
Unqiue Words: 2437

2.003 Mikeys
#2. Uncovering the gene machinery of the Amazon River microbiome to degrade rainforest organic matter
Celio Dias Santos-Junior, Hugo Sarmento, Fernando Pellon de Miranda, Flavio Henrique-Silva, Ramiro Logares
The Amazon River receives, from the surrounding rainforest, huge amounts of terrestrial organic matter (TeOM), which is typically resistant to microbial degradation. However, only a small fraction of the TeOM ends up in the ocean, indicating that most of it is degraded in the river. So far, the nature of the genes involved in TeOM degradation and their spatial distributions are barely known. Here, we examined the Amazon River microbiome gene repertoire and found that it contains a substantial gene-novelty, compared to other environments (rivers and rainforest soil). We predicted ~3.7 million non-redundant genes, affiliating mostly to bacteria. The gene-functions involved in TeOM degradation revealed that lignin degradation correlated to tricarboxylates and hemicellulose processing, pointing to higher lignin degradation rates under consumption of labile compounds. We describe the biochemical machinery that could be speeding up the decomposition of recalcitrant compounds in Amazonian waters, previously reported only in incubation...
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biorxivpreprint: Uncovering the gene machinery of the Amazon River microbiome to degrade rainforest organic matter https://t.co/3fefDkaAZK #bioRxiv
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Authors: 5
Total Words: 10202
Unqiue Words: 3693

1.994 Mikeys
#3. Indirect Readout of DNA Controls Filamentation and Activation of a Sequence-Specific Endonuclease
Smarajit Polley, Dmitry Lyumkis, Nancy C Horton
Filament or run-on oligomer formation by enzymes is increasingly recognized as an important phenomenon with potentially unique regulatory properties and biological roles. SgrAI is an allosterically regulated type II restriction endonuclease that forms run-on oligomeric (ROO) filaments with enhanced DNA cleavage activity and altered sequence specificity. Here, we present the 3.5 A cryo-electron microscopy structure of the ROO filament of SgrAI bound to a mimic of cleaved primary site DNA and Mg2+. Large conformational changes stabilize a second metal ion cofactor binding site within the catalytic pocket and facilitate assembling a higher-order enzyme form that is competent for rapid DNA cleavage. The structural changes illuminate the mechanistic origin of hyper-accelerated DNA cleavage activity within the filamentous SgrAI form. An analysis of the protein-DNA interface and the stacking of individual nucleotides reveals how indirect DNA readout within filamentous SgrAI enables recognition of substantially more nucleotide sequences...
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Sample Sizes : None.
Authors: 3
Total Words: 10860
Unqiue Words: 2890

1.972 Mikeys
#4. A newly defined cullin-RING ubiquitin ligase promotes thermotolerance as part of the Intracellular Pathogen Response in C. elegans
Johan Panek, Kirthi C Reddy, Robert J Luallen, Amitkumar Fulzele, Eric J Bennett, Emily R Troemel
Intracellular pathogen infection leads to proteotoxic stress in host organisms. Previously we described a physiological program in the nematode C. elegans called the Intracellular Pathogen Response (IPR), which promotes resistance to proteotoxic stress and appears to be distinct from canonical proteostasis pathways. The IPR is controlled by PALS-22 and PALS-25, proteins of unknown biochemical function, which regulate expression of genes induced by natural intracellular pathogens. We previously showed that pals-22 and pals-25 regulate the mRNA expression of the predicted ubiquitin ligase component cullin cul-6, which promotes thermotolerance in pals-22 mutants. Here we use co-immunoprecipitation studies to define protein-protein interactions in the IPR and show that PALS-22 and PALS-25 physically associate with each other. We also identify a previously uncharacterized RING domain protein in the TRIM family named RCS-1 as a core component that acts with CUL-6 to promote thermotolerance. Furthermore, we show that the Skp-related...
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Authors: 6
Total Words: 0
Unqiue Words: 0

1.91 Mikeys
#5. N-chlorination mediates protective and immunomodulatory effects of oxidized human plasma proteins
Agnes Ulfig, Anton V. Schulz, Alexandra Müller, Natalie Lupilov, Lars I. Leichert
Hypochlorous acid (HOCl), a powerful bactericidal and fungicidal oxidant, is produced by neutrophils to fight infections. To prevent tissue damage at sites of inflammation, excess HOCl is scavenged by serum albumin and other plasma proteins. Here we show that plasma proteins are not only an effective sink for HOCl, but that HOCl-induced N-chlorination converts plasma proteins into chaperone-like holdases that protect other proteins from aggregation. This chaperone-like conversion was reversible by antioxidants and was abrogated by prior methylation of basic amino acids. Furthermore, reversible N-chlorination of basic amino acid side chains is the major factor that converts plasma proteins into efficient activators of immune cells. Finally, HOCl-modified serum albumin was found to act as a pro-survival molecule that protects neutrophils from cell death induced by highly immunogenic foreign antigens. We propose that activation and enhanced persistence of neutrophils mediated by HOCl-modified plasma proteins, resulting in the...
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Sample Sizes : None.
Authors: 5
Total Words: 19996
Unqiue Words: 5498

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