Articles in 2023

Questions remain on the nature of the bioactivity of nitric oxide (NO) synthase signaling despite its wide appreciation. Here the authors describe NO-ferroheme as a vascular signaling species, whose biological activity is unrelated to the release of free nitric oxide, but allows it to travel protected to its main target guanylyl cyclase.

Most miniature Cas12f nucleases have T-rich PAM specificity, restricting their targeting scopes. The cryo-EM structure of the Clostridium novyi Cas12f1 reveals the molecular basis for rare C-rich PAM recognition and enables optimization of sgRNA scaffold to improve CnCas12f1 activity.

Detailed analysis of the structure–activity relationship for cyclin K degraders reveals diverse compounds that acquire glue activity through simultaneous binding to the CDK12 kinase pocket and engagement of several key DDB1 interfacial residues.

Peptide phage display reveals a non-catalytic binding site on the intervening domain of O-GlcNAc transferase. Its roles in substrate recognition, posttranslational modification (PTM) crosstalk and nutrient response provide insight into the function of this cryptic domain.

By solving the cryogenic electron microscopy structures of bacterial calcium-activated potassium channels, Fan et al. report a pathway for blockers to enter the closed pore of the channels through membrane portals rather than through the canonical ion entryway, opening new avenues for drug-targeting this class of channels.

Henneberg et al. developed conformation-specific antibodies enabling probing NEDD8-activated cullin–RING ubiquitin E3 ligase networks in response to extracellular stimuli, metabolic signals and degrader drugs.

Tryptophan hydroxylases have only been known from eukaryotes and are involved in the biosynthesis of serotonin or melatonin. Here, the authors characterize a family of bacterial tryptophan hydroxylases that differ markedly from their eukaryotic counterpart in cofactor and catalytic mechanism.

Homologous to E6AP C-terminus (HECT) E3s forge polyubiquitin chains through multiple reaction steps. A HECT polyubiquitylation cascade was visualized step-by-step, through use of chemical tools and cryo‐EM, and revealed how K48 linkage-specificity is attained by oligomeric UBR5.

Biorefinery of waste biomass provides a sustainable route to produce chemicals and feedstocks. Now, the efficient production of free fatty acids and 3-hydroxypropionic acid from lignocellulose has been achieved via the co-utilization of xylose and glucose from lignocellulose using an engineered yeast.

By developing a genetically encoded biosensor for enzymes that act on O-glycoproteins, Wardman et al. have provided a new method for rapid screening and analysis of these enzymes and performed the first O-glycopeptidase-directed evolution.

Pan, Lu, Feng, Lu et al. demonstrated that CAG repeat expansion RNAs can form gel-like condensates in the cytoplasm and sequester the translation elongation factor eEF2, leading to suppressed global protein synthesis and neurodegeneration-relevant phenotypes.

A fusion and glue platform was developed to determine the cryo-EM structures of GPCRs in diverse states ranging from β2-adrenergic receptors to adhesion receptors.

Functional and length-tunable lipid mimics are computationally designed and co-translationally incorporated into protein in living systems for the gain-of-function study of protein lipidation and the creation of therapeutic candidates.

Most neuropeptides target G-protein-coupled receptors. Now, it has been shown that the tetrapeptide FMRFamide can directly bind and activate a type of ion channel called FMRFamide-activated sodium channels (FaNaCs). This study reports the structure of the FaNaC ion channel in the apo and FMRFamide-bound states and the substrate specificity and possible gating mechanism of FaNaCs.

Cryo-EM structure and dynamics analysis provides a conformational mechanism for tuning of selectivity between calcitonin and amylin receptors through targeted lipid modification of residues 19–22 within the ‘bypass’ motif of amylin peptides.

Asymmetric glucose tracers reveal the simultaneous use and unique benefits of parallel glycolytic pathways. Cells possessing both textbook glycolysis and Entner–Doudoroff glycolysis have a selective advantage in dynamic environments.

Altering the biophysical positioning of endosomes reveals a regulatory mechanism underlying location-biased responses for G-protein-coupled receptors (GPCR)/cyclic AMP (cAMP)-dependent signaling.

Enolase 1 (ENO1) is a critical glycolytic enzyme that plays essential roles in pathological activities. Here, Sun, Suo, Zhang, Shen et al. reveal the nonmetabolic function of ENO1 in liver cancer, where ENO1 promotes YAP1 mRNA translation to activate arachidonic acid metabolism thus promoting cancer growth.

A pivotal role for beta-1 adrenergic receptor (β1AR) subcellular signaling in controlling cardiac relaxation response through the generation of cyclic adenosine monophosphate (cAMP) and activation of local protein kinase A (PKA) effectors was revealed in cardiomyocytes and in intact zebrafish and mice hearts.

Three-dimensional imaging reveals the existence of GPCR domains at the plasma membrane of living cells. The molecular mechanism underlying this spatial organization is energetic coupling of receptors to the curvature of the plasma membrane.