Articles in 2015

Bioinformatic and biochemical analyses define a conserved domain present in the biosynthetic clusters for ribosomally synthesized and post-translationally modified peptides (RiPPs) that recognizes the leader peptide and thus controls downstream processing.

The p30 isoform of C/EBPα associated with leukemia interacts with WDR5, a component of the SET/MLL histone methyltransferase complex. A small molecule, OICR-9429, disrupted p30-WDR5 interactions, resulting in differentiation of p30-expressing leukemia cells.

A bioinformatics pipeline guided by genomic hints of where to look led to the identification and validation of several new classes of self-cleaving ribozymes and several catalytic RNA motifs related to the known hammerhead or HDV ribozymes.

Tus protein bound to Ter sites on circular bacterial chromosomes provides a way to avoid random crashes of opposing replication forks. DNA-unzipping experiments show that the Tus–Ter–induced lock during unzipping at the nonpermissive face requires only DNA-strand separation.

A fusion protein containing P450 and aldo-keto reductase domains is shown to catalyze reticuline isomerization, the critical branch point between the noscapine and morphine biosynthetic pathways. This discovery completes the enzymatic route to morphine and related compounds.

Structural, spectroscopic and kinetic analyses suggest that class II benzoyl-CoA reductases from anaerobic bacteria use an unusual tungsten cofactor and a conserved histidine to perform a reduction akin to the widely used Birch reduction in organic chemistry.

Structural and biochemical analysis of the heterocyclase that acts on a ribosomally synthesized and post-translationally modified peptide identifies the basis for leader peptide activation and facilitates engineering of a constitutively active enzyme.

Pseudouridine (ψ) is a C-linked uracil modification originally discovered in tRNA. MS analysis and CeU-Seq, a method that permits chemical tagging, pulldown and sequencing of ψ residues, reveal that these modifications are more abundant in the mammalian transcriptome than previously thought.

Carotenoid biosynthesis requires isomerization of the central double bond. Informatic, spectroscopic and functional characterization of Z-ISO, a protein involved in the process, demonstrates that it is a standalone enzyme with unusual heme-dependent chemistry.

The use of a high-affinity VHL ligand allows the development of chimeric molecules that promote the association of ERRα or RIPK2 with the VHL E3 ubiquitin ligase complex, resulting in protein degradation.

The squid beak displays a 200-fold stiffness gradient across its length. A battery of experiments, including ‘omics analysis and rheological measurements, now identifies two protein families that infiltrate and cross-link a porous chitin network to generate variable stiffness.

A computational analysis of cryo-EM data defines the binding mode of capsaicin on TRPV1. A mutational analysis validates these findings, showing specific van der Waals and hydrogen-bonding interactions with the head, neck and tail regions of capsaicin.

An amphotericin antifungal that is less toxic to human cells due to its increased capacity for binding the fungal ergosterol over the human cholesterol can still evade resistance mechanisms, challenging the resistance-toxicity yin-yang of antimicrobials.

A newly engineered phosphoserine synthetase/tRNA pair allows quantitative insertion of phosphoserine or, when coupled with metabolic rewiring, a non-hydrolyzable analog into protein sequences, leading to high yields of modified constructs for functional analysis.

A high-throughput screen identified a small molecule that promoted inclusion of SMN2 exon 7, increased SMN2 protein levels and extended survival in a SMA mouse model through stabilization of the interaction between SMN2 pre-mRNA and U1 snRNP complex.

Structural changes in the capping groups of inverted cyanoacrylamide-based kinase inhibitors resulted in alterations in residence time, with some compounds exhibiting sustained pharmacological effects in vivo.

NO₂⁻ has been viewed primarily as a reservoir for NO and NO-modified species, activated by acids or metal catalysis. Isotopic labeling of NO and NO₂⁻ modifications in vitro and in vivo now demonstrates that NO₂⁻ also participates directly in these reactions through a symmetric N₂O₃ intermediate.

The biosynthesis of benzylisoquinoline alkaloids such as morphine requires tyrosine oxidases, which are prone to overoxidation. A colorimetric readout that co-opts betaxanthin enzymes now enables discovery of an improved oxidase that, with other enzymes, makes reticuline in yeast.

Topoisomerase inhibitors are genome-targeting drugs that induce DNA double-strand breaks or evict histones at sites of action. Genomic mapping of their target sites by ChIP-Seq and FAIRE-Seq and integration with ENCODE data identifies the target specificities of topoisomerase inhibitors and suggests ways to optimize their therapeutic properties.

Fusion of HIV with target membranes via the HIV fusion peptide requires phase separation among lipids as well as phase heterogeneity because the fusion is biased toward the boundary between regions of ordered (so-called rafts) and disordered lipids.