Volume 31 Issue 3, March 2024

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.

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.

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.

Using cryo-electron microscopy the authors show that PtuA, an ATPase, and PtuB, a nuclease, assemble into a supramolecular complex with a stoichiometry of 6:2 for anti-phage defense in bacteria. Nucleoside triphosphates inhibit PtuAB activity while phage infection activates PtuAB to cleave phage genome for immune defense.

Here, using deep mutagenesis and cryo-EM, the authors unveil an autoinhibited conformation of a clamp loader from T4 bacteriophage, which is characterized by disassembled catalytic sites and blocked DNA binding.

Here, the authors solve structures of human DHHC9 with accessory protein GCP16 and their yeast counterpart Erf2–Erf4. The work provides insights into regulation of Ras proteins by palmitoylation, showing that accessory proteins are not involved in catalysis.

In this study, Asami et al. present the cryo-EM structure of the complex between hepatitis B virus protein and its host entry receptor NTCP, which provide a blueprint for the rational design of anti-HBV drugs targeting virus entry.

The authors report the structure of a human 48S translation initiation complex, finding a second molecule of eIF4A at the mRNA entry site, apart from the one present within the cap-binding complex eIF4F. This second entry-site eIF4A may be responsible for unwinding mRNA secondary structure.

Here the authors reveal the role of integrin αV and its β-propeller domain in cancer maintenance and identify a novel class of inhibitors that disrupt integrin heterodimer stability via a CRISPR-tiling-instructed computer-aided (CRISPR-TICA) pipeline.

Here, the authors elucidate how sequential activities of opposite-polarity microtubule motors are coordinated on a cargo, by showing how the Tm1 protein inhibits kinesin-1 during delivery of oskar RNA into the Drosophila oocyte by dynein.

Here, by sub-kb Hi-C and chromosome engineering, the authors visualize bacterial transcriptional units, showing that they form transcription-induced domains. Transcription-induced domains enforce constraints on nearby sequences, affecting their localization and dynamics.

Here, the authors provide mechanistic insights into how decitabine-induced DNA hypomethylation can potentially overcome endocrine resistance in ER+ breast cancer, by targeting the 3D epigenome to resolve gene deregulation and suppress tumor growth.

Using targeted proteomics, the authors reveal concurrent mitotic binding of nuclear receptors, a super-family of transcription factors that emerge as recurrent mitotic bookmarking factors, promoting the reactivation of the pluripotency network in embryonic stem cells.

Using a combination of bioinformatics, biochemistry, genetics, genomics and cell-based approaches, this study shows that the H3–H4 binding capacity of the histone chaperone SPT2 is required to preserve chromatin structure and function in Metazoa.

Here the authors visualize the workings of ELOF1 in transcription-coupled DNA repair, showing that ELOF1 repositions repair factors on the surface of DNA damage-stalled RNA polymerase II to facilitate its ubiquitylation by the CRL4^CSA E3 ligase and inactivation by UVSSA.

By investigating key transcription factors in Drosophila, the authors show that pioneering activity is not an intrinsic, binary property. Instead, it is heavily influenced by the level of chromatin occupancy of the transcription factors, which is controlled by multiple protein domains and protein-extrinsic features.

Here, the authors ask how much regulatory activity DNA is expected to have in the absence of selection. In yeast and humans, they find that gene regulatory activity is common in evolutionarily naive DNA, suggesting that activity is not always indicative of function.

Isaac et al. present mtFiber-seq, a method that measures individual mitochondrial genome packaging at nucleotide resolution. They show that most nucleoids are in an inaccessible state, modulated by the abundance of the DNA-binding protein TFAM.