Articles in 2016

A monobody was identified that binds to an allosteric lobe at the α4-β6-α5 interface to block H- and K-RAS signaling and transformation by disrupting RAS dimerization and nanoclustering.

Inhibitors of the post-proline-cleaving serine proteases DPP8 and DPP9 trigger a lytic form of programmed cell death called pyroptosis by activating pro-caspase-1 without autoproteolysis.

Carbapenem β-lactam antibiotics target non-classical transpeptidases, the L,D-transpeptidases, which act in an alternative Mycobacterium tuberculosis peptidoglycan synthesis pathway, informing the design of evolved carbapenems with improved antibacterial activity.

Small-molecule control of transcriptional activation and genome editing was achieved by tethering inducible protein degron domains to an engineered CRISPR–Cas9 system.

A genetic screening approach using chemically mutagenized haploid mouse embryonic stem cells combined with next-generation sequencing identified recessive suppressor point mutations that elicit resistance to 6-thioguanine.

Aggregated mass spectral data by consortia such as the Global Natural Products Social (GNPS) molecular networking infrastructure enable natural product discovery. DEREPLICATOR, validated on peptidic natural products, is a computational tool to identify known metabolites in complex samples.

Mass spectrometry analysis of stromal extracts reveal a peptidolytic cascade in the plant chloroplast consisting of oligopeptidases and aminopeptidases that mediates the complete degradation of signal peptides to free amino acids.

A systems-level look at the activation of joint synovial fibroblasts in rheumatoid arthritis patients in response to different activators and therapeutic kinase inhibitors shows that multivariate inhibitor effects depend on the nature of the activator, not on the disease state per se.

Structural and biochemical studies of the histone acetyltransferase p300 in complex with acyl-CoA substrates reveal a lysine binding channel that accommodates a particular chain length to mediate efficient histone modification.

Structural insights demonstrating small-molecule-mediated dimerization of BRD4 bromodomains led to the development of biBET, a compound that potently inhibits BRD4–acetyl-lysine interactions by bivalent binding to tandem bromodomains.

A fragment-based design approach identifies reversible inhibitors targeting human protease complement factor D (FD), which is required for amplification of complement C3 signaling. FD inhibitors act as systemic regulators of complement activation in vivo.

Structural and biophysical analysis of the histone acetyltransferase MOZ double PHD finger (DPF) domain reveal that DPF exhibits strong binding preference for crotonylated Lys14 in histone H3 (H3K14) and are co-localized in cells.

Targeting the acetyllysine ‘reader’ activity of BET family transcriptional coactivators has emerged as an anticancer modality. A new class of dimeric JQ1 derivatives displays enhanced potency for bivalent targeting of tandem bromodomains in BET proteins.

The mechanisms by which proteins evolve new functions can be slow and mysterious. Comprehensive structural analysis of enzyme variants reveal how gradual enrichments of pre-existing populations with the right productive dynamics for new functions can accomplish this aim.

A novel approach recruits the largest prokaryotic family of ligand-induced transcriptional regulators to develop a new class of biosensors in yeast based on transcriptional activation, vastly expanding the repertoire of biosensors that could function in eukaryotic hosts.

Proteolytic maturation of an important transcriptional regulator is performed by a glycosyltransferase. The reaction involves glycosylation of a glutamate residue and conversion of the γ-glycosyl ester product into an N-acyl pyroglutamate, which undergoes spontaneous hydrolysis to effect peptide backbone fission.