Structure–function

Translation is controlled mainly during its initiation. Recent studies in yeast and mammals provide new insights into the mechanism of translation initiation regulation in health and in various diseases, and open avenues for the development of innovative therapies targeting the translation machinery.

Mechanistic target of rapamycin mTOR complex 1 (mTORC1) is a central regulator of cellular metabolism. Recent studies of the molecular architecture of mTORC1 shed new light on its physiological functions and on the consequences of their dysregulation in cancer, type 2 diabetes and neurodegeneration.

All aspects of gene regulation involve RNA helicases, which bind or remodel RNA and RNA–protein complexes. Recent data establish a link between helicase structure, mechanism of function and biological roles, including in diseases such as cancer and neurological disorders, with implications for the design of small-molecule inhibitors.

The proteins apoptosis regulator BAX (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-2-related ovarian killer protein (BOK), gasdermins and mixed lineage kinase domain-like protein (MLKL) are key executioners of regulated cell death by forming pores across the plasma or mitochondrial membrane. This Review discusses structural rearrangements during activation and oligomerization of these proteins and highlights commonalities and differences of pore formation mechanisms.

Despite the crucial roles of Hedgehog signalling in development and tissue regeneration, aspects of the Hedgehog signalling mechanism have been uncovered only recently. These studies reveal a central role for lipids in the Hedgehog signal activity, and provide new insights into the therapeutic potential of modulating Hedgehog signalling in tissue regeneration.

Nuclear transcription of a wide variety of RNA species is conducted mainly by three RNA polymerases, which are large and dynamic protein complexes. Recent structural studies have provided important insights into the activities at different transcription stages and the commonalities and differences between these transcription machineries.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses rely on a cohort of specialized viral proteins to transcribe and replicate their RNA genomes. Recent studies have improved our understanding of coronavirus RNA translation, replication and transcription, and offer new therapeutic targets.

Recently determined structures of the telomere maintenance protein complexes shelterin and CST shed new light on the regulation of telomere DNA replication and chromosome end-capping, and on how disease-causing mutations in their encoding genes may affect their functions.

Embedded within the complexity of biological systems lies a formidable task: deciphering the intricate architecture of macromolecules. In this Viewpoint, a panel of experts discuss the key challenges and opportunities of macromolecular structure determination, highlighting the crucial synergy between empirical experimentation and artificial intelligence-based techniques in unravelling these complexities.

A Comment on the impact of improved protein structure prediction by Kathryn Tunyasuvunakool from DeepMind — the company behind AlphaFold.