The microtubule motor dynein is regulated by lissencephaly-1 (Lis1) at several points during its complex activation process. Two papers reveal the molecular mechanism for two steps: the beginning, when Lis1 acts as a wedge to disrupt dynein’s autoinhibited conformation; and the end, when microtubule binding ejects Lis1 from the motor.

New cryo-electron microscopy (cryo-EM) structures of CDP- and CDP-choline-bound choline phosphotransferase 1 (CHPT1) and choline/ethanolamine phosphotransferase 1 (CEPT1), involved in the metabolism of the two main lipids in eukaryotic cell membranes, capture the membrane proteins at resolution <4 Å, sufficient to gain mechanistic insights into these enzymes.

The development of an epigenetics-focused, CRISPR-based high-content functional genomics screening platform provides insight into chromatin regulation and uncovers a potential strategy to treat an aggressive type of leukemia.

New work shows that in mammals, the iDDR motif of telomere factor TRF2 inhibits the MRE11–RAD50–NBS1 (MRN) complex at chromosome ends through a direct iDDR–RAD50 interaction. Unrelated protein motifs in yeasts inhibit MRN functions via an analogous mechanism, suggesting a convergent evolution in eukaryotes to control MRN action at telomeres.

This study shows that CRISPRi mediates precise transcriptional pausing, which can be followed by transcription termination. The pausing effect is asymmetric, only being induced when dCas9-bound guide RNA anneals to the non-template DNA strand.

The authors present the full-length dimeric TRIM72 E3 ubiquitin ligase and the architecture of its high-order assembly bound to a phosphatidylserine-enriched membrane, providing insights into its role in membrane repair and ubiquitylation.

This study describes an approach to segment and extract key biophysical parameters from live-cell three-dimensional single-molecule imaging trajectories. The authors use this approach to study how NuRD assembles on chromatin and how it regulates enhancer dynamics.

Here, the authors constructed a deep-learning approach to design closed repeat proteins with central binding pockets—a step towards designing proteins to specifically bind small molecules.

The authors solved the cryo-EM structure of Myomaker, essential for myoblast fusion, and showed that it adopts a GPCR-like fold. They pinpointed the role of the dimeric interface and lipid-binding sites for fusion, and proposed a mechanism that may be conserved between species.

Release of inorganic phosphate (P_i) from actin marks older actin filaments for disassembly. Here, the authors show how P_i exits the F-actin interior through a ‘molecular backdoor’. The backdoor arrangement is distorted in a disease-linked actin variant.

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.