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Under steady-state conditions, the E3 ubiquitin ligase Parkin is localized to the cytosol in an autoinhibited state. Two recent studies describe the mechanism of Parkin activation by phosphorylation via structural rearrangement of the Ubl and RING2 domains, explaining how the RING2 domain is released from the core of Parkin to allow for ubiquitination of its substrates.
In a stress-free environment, the histone binding function of 53BP1 is inhibited by TIRR, but upon DNA damage 53BP1 is recruited to chromatin and promotes DNA repair. New structural studies provide insights into the mechanisms underlying 53BP1 inhibition and activation. TIRR physically blocks the methyl-lysine histone-binding site of Tudors, and RNA binding by TIRR alleviates this block.
Activation signals from GPCRs, the largest receptor family, are transmitted to heterotrimeric G proteins and arrestins, and can be differentially modulated by GPCR phosphorylation. In a recent article, available data, including multiple arrestin structures, are analyzed to decipher common and state-specific conformational changes in arrestins and how these depend on patterns of receptor phosphorylation.
Bhat and Cortez discuss current knowledge on the multiple mechanisms by which RPA and RAD51 contribute to genome stability during DNA replication, in particular for replication fork reversal and fork protection.
Traditional approaches to covalent drug design postulate that noncovalent binding affinity (Ki) should be in the nanomolar range for the lead compound to be attractive. A study by Hansen et al. suggests that covalent K-Ras inhibitors can have weak noncovalent binding affinity yet have fast chemical reactivity (kinact), because K-Ras enhances the covalent reactivity of bound inhibitor, similarly to how enzymes activate their substrates.
Rittinger and Walden review recent structural and functional insights to contrast and compare RBR E3 ubiquitin ligases and their regulation through autoinhibition, post-translational modifications, multimerization and protein-protein interactions.
Developments in basic RNA biology have spawned RNA-based strategies to generate new types of therapeutics. Judy Lieberman reviews RNA-based drug design and discusses barriers to more widespread applications and possible ways to overcome them.
Recent developments in transcriptome-wide sequencing technologies have enabled the identification of cellular mRNA decay intermediates. Although canonical mRNA decay has been shown to occur by deadenylation followed by decapping and subsequent exonucleolytic decay from both mRNA ends, a study by Mourelatos and colleagues now defines mRNA fragments that are generated on polysomes by endonucleolytic cleavages phased by the associated ribosome.
Inheritance of Polycomb repressive complex 2 (PRC2)-mediated gene silencing involves self-propagation of histone H3 lysine 27 (H3K27) methylation from an initial nucleation site, but how the first H3K27 methylation marks are established is not fully understood. A recent study reveals that PRC2 can reconstitute H3K27 methylation de novo in cells that have lost the mark. This reconstitution is dependent on the PRC2 core component SUZ12, which provides a novel link between initiation and self-propagation of this critical epigenetic mark.
A new study reveals how the oocyte-specific transcription factor TAp63 ensures female germ line fidelity and describes approaches to circumvent premature ovarian insufficiency in women receiving cytotoxic chemotherapy.
Transcripts with highly complementary sequences can target microRNAs (miRNAs) for degradation, but the physiological relevance of target-directed miRNA degradation (TDMD) has remained unclear. Bitetti et al. now identify a conserved vertebrate RNA that induces TDMD in the cerebellum of zebrafish and mouse to promote wild-type animal behaviors.
Nanobodies have emerged as highly versatile and useful binding molecules in biomedical research. A technical report describes a cost- and time-effective in vitro platform that facilitates the generation of desired nanobodies, including conformationally selective nanobodies against agonist-bound G-protein-coupled receptors (GPCRs).
Wu and Wilson review our structural knowledge of influenza virus HA and broadly neutralizing antibodies, which have opened the way for design of novel vaccines and therapeutics.
In this Review, the authors discuss our current understanding of how the hexameric helicases that catalyze helix unwinding during DNA replication are physically and functionally integrated with other replisome components.
Chd1 is a highly conserved chromatin remodeler found across all eukaryotic species. A recent study shows the structural changes that take place when yeast Chd1 binds to its nucleosomal substrate and reveals how they relate to remodeler function.
In this Review, the authors discuss recent insights into the mechanism of GPCR signaling provided by structural and biophysical elucidation of receptor interactions with G proteins and arrestins.
Rossmann and colleagues review the rapid progress in our understanding of the structure of Zika virus, building on previous studies of other flaviviruses such as dengue virus.
