In this Review, the authors present an overview of our current understanding of the relationship between DNA methylation and three-dimensional chromatin architecture, discussing the extent to which DNA methylation may regulate the folding of the genome.

Here, the authors discuss the various roles of the HUSH transcriptional silencing complex and its dysregulation in disease.

Ubiquitination is an essential process that curtails cellular levels of damaged and redundant proteins. Chemical biologists have harnessed this natural system to induce the degradation of disease-relevant proteins. We reflect here on the potential of ‘degraders’ for targeted selectivity, and discuss the role of computer-aided drug design in shaping future advances.

The Gabija system constitutes one of the most prevalent anti-phage defense systems and is composed of GajA and GajB. Here, using cryo-EM and biochemistry, the authors show that GajA and GajB form a supramolecular complex with a stoichiometry of 4:4 to promote anti-phage defense.

The authors report that the γ-tubulin ring complex (γ-TuRC), an essential regulator of microtubule formation, selectively nucleates microtubules with 13-protofilaments and characterize the structural transformations associated with this function.

Using cryo-electron tomography, Dendooven et al. determined the structure of the native budding yeast γ-tubulin ring complex (γTuRC) capping spindle microtubules and showed that γTuRC adopts an active closed conformation to function as a perfect geometric template for microtubule nucleation.

Here, using cryo-EM, biochemistry and cell biology, the authors reveal the unique assembly, catalytic mechanism, multimodal substrate recruitment and regulation of the atypical ubiquitin ligase complex CUL9–RBX1.

Precise protease positioning and gating of the proteasome core require the ordered assembly of 28 subunits. Cryo-EM structures of seven intermediates visualize five dedicated chaperones and three propeptides mediating step-by-step assembly of the human 20S proteasome.

To prevent promiscuous protein degradation, proteasomes are initially assembled as inactive complexes. Their activation is autocatalytic and coupled to assembly. Here the authors uncover key aspects of the autocatalytic activation mechanism.

G protein-coupled receptors (GPCRs) with no known endogenous ligand are termed orphans. Deorphanization of a GPCR involves identifying the ligand, which can be a painstaking exercise. In this Comment, we discuss the challenges in the process, its role in drug discovery and alternative approaches to characterizing orphan GPCRs.

The identification of sodium and potassium currents as underlying action potential propagation, more than 70 years ago, opened a new avenue of research into the role of ion channels. In this Comment, we present our personal perspectives of the field, from the identification of Shaker as a potential potassium channel to the mechanistic insights available to us today.

In addition to the usual dose of compelling science, our March issue features thoughtful reflections on the last 30 years from readers, as well as past and present editors. Perhaps influenced by these pieces or by our stunning cover — or maybe it is just the changing seasons — we are in an introspective mood this month.

Over the past 30 years, Nature Structural & Molecular Biology (NSMB) has covered an enormous breadth of subjects in the broad field of molecular and structural biology. Here, some of the journal’s past and present editors recount their editorial experience at NSMB and some of the more memorable papers they worked on.

Over the past 30 years, the field of structural biology and its associated biological insights have seen amazing progress. In this Comment, I recount several milestones in the field and how we can apply lessons from the past toward an exciting future, especially as it relates to drug discovery.