Articles in 2023

The use of chemical proteomics and cell-based assays enabled the discovery of gut microbiota-derived aromatic monoamines and synthetic agonists for an orphan G protein-coupled receptor GPRC5A that stimulated beta-arrestin recruitment.

Chemoproteomics reveals a vast expanse of ligandable cysteine sulfenic acids in the human proteome, highlighting the utility of nucleophilic small molecules in the fragment-based covalent ligand discovery pipeline.

Lowering the levels of disease-promoting proteins is generally assumed to be beneficial. The authors developed a two-step strategy to integrate protein-level tuning, noise-aware synthetic gene circuits into a well-defined human genomic locus. This approach was used to study the effect of BACH1 levels on MDA-MB-231 human breast metastatic cells.

Using a neural network trained on bacterial growth inhibition data, in silico prediction of molecules with activity against Acinetobacter baumannii led to the identification of the narrow-spectrum abaucin, which perturbs lipoprotein trafficking.

The structure, molecular and mechanistic details of the human α1,3-fucosyltransferase FUT9 provide insight into the synthesis of diverse and modified glycan-capping Lewis antigen structures by a conserved family of mammalian fucosyltransferases.

The medicinal plant Catharanthus roseus is a source of leading anticancer drugs. The monoterpene indole alkaloid (MIA) biosynthetic pathway in C. roseus has now been analyzed using a complementary, multi-omics, single-cell approach. This identified clusters of genes involved in MIA biosynthesis and cell-type-specific partitioning in the MIA biosynthetic pathway.

Identification of the molecular features that define the kinetic stability of the clinically relevant NDM-1 metallo-β-lactamase in the bacterial periplasm links the cellular metabolism of this protein with its natural evolution.

A combination of enzyme discovery for nonheme diiron N-monooxygenases, metabolic engineering and genetic code expansion enables the construction of a live bacterial producer of synthetic nitrated proteins containing para-nitro-l-phenylalanine.

Cryo-EM structures of complement receptors C3aR and C5aR1 bound to their respective anaphylatoxin ligands C3a and C5a reveal insights into the conserved features and topological diversities of C3aR and C5aR1 in recognizing C3a and C5a.

Itskanov and Wang et al. determined high-resolution structures of the human Sec61 channel inhibited by several structurally distinct small molecules and revealed the common inhibitor-binding site in Sec61 and molecular interactions in atomic detail.

A selective inhibitor of Sec61 blocks protein entry into the secretory pathway and has therapeutic efficacy in rheumatoid arthritis. A cryo-EM structure of the inhibited Sec61 provides a model for client-selective protein translocation inhibition.

The bacterium Proteus mirabilis natively forms a bullseye colony pattern by swarming. Doshi et al. engineered this bacterium to encode environmental inputs, including copper, into its pattern features, and decoded them with image processing and deep learning.

By using a combined computational and experimental approach, peptide exchange of 12 abundant MHC-II allotypes is shown to maintain responsiveness to HLA-DM catalysis. HLA-DM susceptibility is postulated to contribute to disease association.

A resistance mechanism for a class of drugs targeting histone acetyltransferase inhibitors was identified where metabolic rewiring creates high concentrations of acetyl-CoA that outcompete drug-target engagement.

Replicative errors contribute to genetic diversity needed for evolution but in high frequency lead to genomic stability. Here, NMR is used to show via a kinetic model that DNA dynamics can determine the misincorporation of A•G and A•8OG mismatches.

Characterization of the conformation landscape of the bacterial ABC transporter CydDC reveals that this heterodimeric protein complex is a long-sought heme transporter essential for the functional maturation of bd-type cytochromes.

The RXFP1 relaxin receptor is a critical mediator of physiological adaptation to pregnancy and an emerging drug target. RXFP1 activation was found to entail an unexpected mechanism of ectodomain disinhibition resulting in downstream signaling.

Development of a novel spatial transcriptomics method, RAINBOW-seq, enables probing of the heterogeneity in a bacterial community, revealing rich coordination of metabolism in the E. coli biofilm to mediate collective fitness.

De novo designed interleukin-4 mimetics were engineered that induce biased signaling activation and exhibit high thermal stability. These mimetics offer insight into cytokine signaling and can be directly incorporated into 3D-printed biomaterials

Super-resolution imaging detects plasma membrane domains that emerge when receptors are clustered in live B cells. Domain structures arise due to the membrane phase transition and can tune local membrane organization and receptor activation.