The Review provides an overview of ion-channel insecticide targets, with a focus on their mechanisms of action, and offers a perspective for structure-based development of insecticides.

Cells maintain homeostasis under stress conditions by minimizing damages, maintaining structural integrity and modifying the activity of macromolecules and signaling molecules such as kinases and phosphatases. Though a comprehensive view of how stress-regulated signaling pathways regulate cell survival remains elusive, new work sheds some light.

Ferroptosis suppressor protein 1 (FSP1, or AIFM2), an NADPH quinone reductase noted to protect cancer cells from ferroptosis, acts in FAD/NADPH binding and proton transfer. Recent papers assess its evolutionarily conserved sites via mutagenesis and define its inhibition as an off-target mediator of brequinar-mediated ferroptosis sensitization.

OAT1 has a fundamental role in the kidney by facilitating the urinary excretion of various drugs and endogenous metabolites. Two studies now present high-resolution structures of OAT1 using cryo-EM, elucidating its intricate polyspecific transport capabilities and paving the way for structure-based drug research and development.

Here, using CAGE-seq, the authors show that transcription start site choice in thousands of genes may endow transcripts with distinct post-transcriptional fates, with dynamic switching defining cancer cell proliferation, differentiation and treatment response.

Here the authors show that, in the absence of Pi3K–AKT–mTOR signaling, AGO2 accumulates in the nucleus of quiescent cells, where it binds to young retrotransposons and represses their expression.

Mao et al. reported ribosomal frameshifting events shortly after start codon selection, which is influenced by the sequence context and controlled by initiation factor eIF5B. This translational ‘noise’ is increased in response to nutrient starvation.

Extensive mutational analyses of ferroptosis suppressor protein-1 (FSP1) reveal its molecular mechanism in ferroptosis prevention and uncover the mechanism of action of the FSP1 inhibitor iFSP1 and a new species-independent FSP1 inhibitor, viFSP1.

Many multipass membrane proteins are not fully inserted into the membrane when translation ends. Wu et al. now show that a membrane insertase called EMC can facilitate maturation of these proteins by post-translationally completing their insertion.

Cryogenic electron microscopy structures reveal how the immunophilin co-chaperones, FKBP51 and FKBP52, each engage Hsp90–client complexes to directly stabilize a folded, ligand-bound client, the glucocorticoid receptor, and promote the next stage of client maturation.

DNA polymerase θ (POLQ) repairs mitotic DNA breaks; this requires RHINO and PLK1, averts genomic instability and may underlie effects of POLQ inhibitors in HDR-deficient cancer cells. We discuss recent work on mitotic DNA break processing and repair, the need for multiple DSB repair pathways and implications of therapeutic POLQ targeting in cancer.

In January 2024, Nature Structural & Molecular Biology (NSMB) will celebrate the 30^th anniversary of publishing its first issue. Though initially launched as Nature Structural Biology in 1994, the journal has since expanded its scope to include all research into the molecular underpinnings of life, with the vision that the broadest insight can be gleaned through a suite of complementary approaches.

Understanding the underlying molecular mechanisms of dosage compensation and how cells equalize gene expression from the sex chromosomes has interested scientists for more than six decades. However, with so many questions still unanswered, the field continues to capture the attention of researchers.