Volume 20 Issue 1, January 2024

Protein lipidation is an important post-translational modification that can be difficult to study. New amino acids with side chains that mimic naturally occurring lipid modifications stand to facilitate the study of lipidated proteins.

A universally effective method has been developed to enable cryo-electron microscopy structural determination of G protein–coupled receptors in various states. This method will accelerate structure-based drug discovery and enhance understanding of the activation mechanism for these receptors.

Cyclic tetrapeptides (CTPs) have great potential for materials and therapeutics; however, synthesizing these molecules remains a significant challenge. Now, an enzyme has been developed that enables efficient N-to-C cyclization of linear tetrapeptidyl substrates to form structurally diverse CTPs.

Analyzing glycans is challenging because of their structural diversity and complexity and the lack of analytical techniques capable of resolving pools of similar glycan structures. A new method now enables imaging of single glycans, providing direct observation of individual glycans and glycoconjugates.

Controlled interactions between macromolecules are fundamental regulatory layers. Hijacking these circuits via proximity-inducing small molecules offers many therapeutic opportunities. The organizers, Georg Winter and Cristina Mayor-Ruiz, report on the latest trends in this emerging field discussed at the 39th IRB-BioMed Conference in Barcelona.

We developed a versatile lipid probe — MAO–SiR — to visualize the structure and dynamics of the inner mitochondrial membrane (IMM). MAO–SiR assembles in situ from two cell-permeant small molecules to image the IMM selectively, continuously and at super resolution for extended periods of time without extensive photobleaching or toxicity.

By investigating the structure–activity relationship of molecular glue degraders that target cyclin K, we discovered that a wide range of compounds, including known kinase inhibitors, possess this gain-of-function activity. These findings provide insights that might enable more rational design and optimization of molecular glue compounds.

Phosphoribosyl pyrophosphate synthetase (PRPS1), an enzyme that regulates de novo nucleotide synthesis, was found to be O-GlcNAcylated, which increases PRPS1 activity, and is associated with increased tumorigenesis and resistance to chemoradiotherapy.

Phage and yeast display were used to generate variable heavy single-domain antibodies that bind and allosterically inhibit ectodomain phosphatase/phosphodiesterase-1 to increase the half-life of the immune-stimulant cyclic guanosine monophosphate adenosine monophosphate (cGAMP) in tumor microenvironments.

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.

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.

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.

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.

A lipid-like small molecule, MAO-N₃, was developed to assemble inner mitochondrial membrane-specific probes for confocal and various super-resolution microscopy techniques, with significantly improved time-lapse capability and minimal toxicity.

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.

Park et al. redesigned the abscisic acid-induced dimerization module to respond to diverse ligands and function orthogonally to the natural modules, enabling synthetic biological circuit design in plants and yeast.

Oxygen sensitivity hampers applications of metal-dependent CO₂ reductases. Here, Oliveira et al. describe how an allosteric disulfide bond controls the activity of a CO₂ reductase, preventing its physiological reduction during transient O₂ exposure and allowing aerobic handling of the enzyme.

Macrocyclic peptides are promising scaffolds for chemical tools and potential therapeutics, but their synthesis is currently difficult. Here, the authors report the characterization of Ulm16, a peptide cyclase of the penicillin-binding protein (PBP)-type class of thioesterases, that catalyzes head-to-tail macrolactamization of nonribosmal peptides of 4–6 amino acids in length.