Articles in 2022

The combination of cryo-electron microscopy analysis with cell-signaling assays revealed promiscuous G_i/G_q coupling of somatostatin receptors and molecular mechanism of ligand-dependent selective G protein signaling

By inserting RNA-binding domains to an active-site-proximal loop amidst CRISPR–Cas, Yang, Song et al. generate variants with enhanced collateral activity for ultrasensitive and amplification-free RNA detection when coupled with electrochemical sensing platforms.

Single-molecule methods are a powerful tool to study the kinetics of ATP-powered enzymes. A method that locally controls the generation of ATP significantly increases the throughput of single-molecule approaches and unlocks single-turnover analysis of molecular machines.

Artificial intelligence (AI) is poised to transform therapeutic science. Therapeutics Data Commons is an initiative to access and evaluate AI capability across therapeutic modalities and stages of discovery, establishing a foundation for understanding which AI methods are most suitable and why.

A new method for controlling NTP-driven reactions in single-molecule experiments via the local generation of NTPs (LAGOON) markedly increases the measurement throughput and enables single-turnover observations.

Enzymatically generated sulfane sulfur species called hydropersulfides terminate free radical chain reactions to prevent oxidative membrane damage and ferroptosis induction.

Polyketides are assembled by modular polyketide synthases and undergo chemical tailoring reactions. A dehydratase domain variant catalyzes two sequential elimination reactions from thioester intermediates to produce conjugated diene modifications.

Compound library screening combined with medicinal chemistry and structural biology approaches enables the development of potent and highly selective cell-permeable small-molecule inhibitors of phosphatidylinositol 3-kinase C2α activity and function.

Isoform-selective inhibition of JAK kinases is of key interest in drug discovery. A novel pocket in the JAK pseudokinase domain was targeted by an allosteric covalent inhibitor, leading to specific JAK1 inhibition and providing a deeper understanding of cytokine signaling.

Chemical proteomics identified covalent ligands targeting an isoform-restricted allosteric cysteine in JAK1. The compounds inhibit JAK1-dependent signaling in immune cells with unprecedented selectivity.

An RNA aptamer that selectively binds FAD over FADH₂ shifted the reduction potential of the bound cofactor, similar to flavoproteins, and was shown through structural characterization to use π–π and donor–π interactions to drive the shift.

SARS-CoV-2 spike-directed, non-neutralizing antibodies were converted into broad-spectrum inhibitors by conjugation to the SARS-CoV-2 receptor, ACE2, resulting in fusion proteins that target all SARS-CoV-2 variants of concern tested.

A tool kit to study bacterial efflux pumps and the movement of compounds across the cell envelope was developed enabling investigation of efflux pump physiological functions, substrate specificities and profiling of efflux pump inhibitors.

Dynamic redundancy by horizontal gene transfer stabilizes gene abundances amidst compositional fluctuations in microbial communities, which suggests a means to program gene stability of complex microbiota.

Engineering of a high-affinity Delta-like variant, named Delta^MAX, potently activates Notch signaling when provided in a bead-bound or cellular format, while administration as a soluble decoy inhibits signaling.

Using methyl group and fluorine NMR spectroscopic methods, Overbeck et al revealed that the dynamics of the eukaryotic 5′→3′ exoribonuclease Xrn2 in the region around the active site are correlated with its catalytic activity.