Volume 19 Issue 6, June 2023

GPCRs are selective for specific G-protein subtypes, thereby ensuring signaling fidelity. A new report finds that that empty-like G-protein mutants are promiscuously recognized by GPCRs, suggesting that receptors select cognate over non-cognate G proteins at steps preceding nucleotide release.

Modern drug discovery relies upon intelligent exploration of ‘in stock’ and ‘on demand’ virtual libraries of compounds. A comparative analysis highlights the explosive expansion of accessible chemical space and also reveals challenges and opportunities arising for computational drug discovery.

The role of lipid membrane domains in the activation of immune cells remains elusive. New microscopy data on B cell signaling support a mechanism in which lipid membrane domains consolidate upon B cell receptor clustering.

Engineering synthetic tools that facilitate decision-making in mammalian cells could enable myriad biomedical applications. Researchers have now developed a new system of inducer-controlled transcription factors to facilitate synthetic decision-making (LOGIC) in human cells based on modular protein-fusion cascades.

Ferroptosis can be induced by lipid peroxidation in various subcellular membranes, including the endoplasmic reticulum (ER), mitochondria and lysosomes. By studying the subcellular distribution of ferroptosis-modulating fatty acids, we observed that the ER is a key initial site of peroxidation, followed by the plasma membrane, whereas other organelles are not as critical for ferroptosis.

This Perspective details how genome-wide association studies and metabolomics enabled the discovery of structures, bioactivities and pathways of modular metabolite biosynthesis originates from the ‘hijacking’ of conserved detoxification mechanisms by nematodes.

Coupling selectivity was found to be partly lost with G proteins that bypass conformations that exist before GDP release, suggesting that selectivity is closely linked to the process of nucleotide release.

The F₄₂₀-dependent sulfite reductase protects some methanogenic archaea by converting toxic sulfite. Structural analysis reveals how the two active centers are electro-connected and provides a plausible picture of a primitive sulfite reductase.

A potent and selective degrader was developed that depletes STAT5 in cells and mouse tissues, exerts cell growth inhibition in cells with activated STAT5 and induces tumor regression in mouse models.

Docking virtual libraries against protein structures has identified potent ligands for multiple targets. A comprehensive analysis reveals that the increased size of virtual libraries improves receptor fit but diverges from bio-like molecules.

Ferroptosis is a lipid-peroxide-driven cell death with promising therapeutic applications. Although peroxidation of various subcellular membranes can initiate ferroptosis, the authors found that the endoplasmic reticulum is an essential site.

Brain imaging using the compact NanoLuc luciferase has been stymied by the lack of suitable substrates. Su et al. report a brain-optimized substrate, cephalofurimazine, and use it to perform non-invasive calcium imaging of neuronal activity.

Development of a generalized method for dual site-specific incorporation of nonnatural photocaged and photoreactive amino acids into proteins expressed in live cells enabled engineering of a photoreactive photoactive antibody fragment.

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.

In contrast to dsDNA phages where multiple genes are involved in programmed host lysis, ssRNA Fiersviridae phages require only a single gene. Here, genome-wide host suppressors of diverse single-gene lysis systems are identified using a high-throughput genetic screen.

The authors show modular functionality of TetR-like proteins in mammalian cells, separating the protein–DNA and the protein–protein interaction. This allows for engineered ON- and OFF-type responses to stimuli, higher order and multi-input logics.

Bifidobacterium bifidum is a member of the human gut microbiome. A new report demonstrates that it can degrade sulfated mucin O-glycans in vivo, and a GH20 sulfoglycosidase possessing a novel GlcNAc-6S-specific carbohydrate-binding module plays a pivotal role.