Volume 16 Issue 1, January 2020

Molecular-glue-mediated proximity-induced degradation now allows unprecedented therapeutic targeting of previously undruggable proteins. Structures showing how aryl-sulfonamides mediate recruitment of the splicing factor RBM39 to the E3 CRL4^DCAF15 broaden the mechanistic principles by which molecular glues target ubiquitylation.

Phenotypic screening is an engine of discovery for bioactive small molecules and can unravel novel mechanisms and pathways controlling cellular physiology. A recent study reveals the CPSF complex as a pharmacologically tractable target of JTE-607 and context-specific cancer dependency.

An in silico directed evolution approach using first principles of allostery predicts the effects of protein sequence and structure variation on constitutive activity and ligand response in GPCRs.

Cryo-EM and crystal structural analysis of DDB1–DCAF15–DDA1 in complex with E7820 and RBM39 reveal that aryl-sulfonamides reshape the surface of the cullin RING ligase substrate receptor DCAF15 to bind and degrade the splicing factor RBM39.

The crystal and cryo-electron microscopy structure analysis of the DCAF15–DDB1–DDA1–indisulam–RBM39 complex revealed the detailed mechanism of action of indisulam-induced RBM39 degradation and defined an α-helical degron motif in RBM39.

A structural look at the interaction between the SH3b domain of the peptidoglycan endopeptidase lysostaphin and the target for its antistaphylococcal activity, peptidoglycan, reveals a mechanism of bacterial cell wall binding.

The cellular stability of an oncogenic factor, AIMP2-DX2, is increased via association with HSP70. Interference with this interaction by a small-molecule compound promotes ubiquitin-mediated degradation of AIMP2-DX2 and reduces cancer cell growth.

Rather than operating linearly like most NRPS–PKS systems, biosynthesis of the thalassospiramide lipopeptides employs intermodule substrate activation and tailoring, module skipping and pass-back chain extension to generate chemical diversity.

The RNA endonuclease CPSF3 was identified as the cellular efficacy target of the small molecule JTE-607, revealing pre-mRNA processing as a vulnerability in cancers such as Ewing’s sarcoma that are characterized by aberrant transcription.

Two bioinformatic tools, BiG-SCAPE and CORASON, enable sequence similarity network and phylogenetic analysis of gene clusters and their families across hundreds of strains and in large datasets, leading to the discovery of new natural products.

A dimerization-induced self-quenching fluorescent dye, Gemini-561, and its aptamer o-Coral were developed for imaging mRNAs in living cells with improved brightness and photostablility.

A computational approach for designing GPCRs with new signaling functions including allosteric signaling properties yielded D2 receptor variants with predictable G-protein signaling responses, some with enhanced potency and responses to dopamine.

Redesign of a glucose dehydrogenase to use nicotinamide mononucleotide (NMN⁺) instead of NAD(P)⁺ enables the development of a noncanonical cofactor system that can be used to support redox chemistries both in vitro and in Escherichia coli.

Microbiota-derived butyrate acylation of the key Salmonella enterica transcriptional regulator HilA attenuates virulence of the bacteria, blocking invasion of epithelial cells in vitro and dissemination in vivo.