In this perspective, the authors showcase the importance and need for additional investigation of the ubiquitin-dependent regulation of neurodevelopment. They then propose interdisciplinary approaches that will allow improved spatiotemporal understanding of this relationship in the context of basic neuroscience and disease.

Szalay et al. discuss cross-kingdom similarities and differences in 3D chromatin folding in relation to gene regulation, including in bacteria, archaea, mammals and plants. This comparison reveals certain factors as ancestral sculptors of the genome, but also that evolution tolerates considerable variety in genome organization.

Racetam anticonvulsants, such as levetiracetam, are widely prescribed to treat and prevent seizures. Despite decades of clinical use, their mechanism of action remains unclear. Two studies now reveal the structure of the racetam-binding protein SV2A in complex with anticonvulsant drugs, providing insights into their mechanism of action and the physiology of neurotransmission.

Autoantibodies targeting glutamatergic N-methyl-d-aspartic acid receptors (NMDARs) are found in people with anti-NMDAR encephalitis. Two studies reveal that patient-derived autoantibodies are diverse in their epitope binding and modes of action on the NMDAR, providing insights into the mechanisms behind autoantibody-induced NMDAR hypofunction.

The authors here show that chromatin interactions during mouse fetal development are spatiotemporally dynamic. Integrating interactomes with other datasets predicts target genes for candidate enhancers and helps interpret noncoding risk variants in the human genome.

Here, the authors describe a noncoding genetic variant in GBA1 specific to people of African ancestry that increases the risk of neurodegenerative diseases by interfering with the splicing of mRNA, resulting in lowered protein levels and activity.

Xue et al. visualize how the antibiotic chloramphenicol reshapes the translation landscape and induces ribosome collision in bacterial cells, illuminating its context-dependent action across atomic, molecular and cellular scales.

The cryo-electron microscopy structures of γ-secretase bound to five anticancer clinical compounds reveal characteristic differences in recognition and suggest strategies for improved drug design.

The authors show cryo-electron microscopy structures of the human high-affinity sodium–dicarboxylate cotransporter, responsible for dicarboxylate import into the cell, in complex with various substrates and in different states establish the basis of substrate recognition, differentiation and release, as well as regulation of transport domain movement.

Here, the authors demonstrate how Mrs2, critical for import of Mg²⁺ into the mitochondria, transitions from open and closed five-fold symmetric states to control the influx of Mg²⁺ using an auto-ligand-gating regulation mechanism.

As 2024 closes, we take this opportunity to reflect on the highlights of our 30th anniversary year and consider what the future holds for the field.