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Engineering of temperature-sensitive DNA repressors led to thermal bioswitches, allowing Escherichia coli to respond sharply to temperature at tunable set points and enabling application to host diagnostics and disease therapy.
ACSL4 is critical for induction of ferroptosis, a programmed form of necrotic cell death, through the production of long polyunsaturated fatty acids that can be inhibited in an in vivo ferroptosis model with a small molecule ACSL4 inhibitor.
Characterization of five enzymes involved in gibberellin production in rhizobia completes the elucidation of its biosynthetic pathway and indicates that bacteria have independently evolved this pathway separate from the ones found in plants and fungi.
Arachidonyl and adrenoyl PE phospholipids generated by ACSL4, an acyl-CoA synthase, are doubly or triply oxidized by lipoxygenases and other iron-containing sources of oxidation to promote ferroptotic cell death.
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.
Unlike their bacterial counterparts, fungal nonribosomal peptide synthetases utilize a terminal condensation-like (CT) domain to form macrocycles, details of which are illuminated by structures of a CT domain and neighboring thiolation domain.
The synthetic bioinformatic natural products (syn-BNPs) approach identifies putative natural products that are validated directly by independent synthesis. Its application led to the identification of humimycins, non-ribosomal peptides that have antimicrobial activity in mice.
