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As 2023 comes to an end, we take this opportunity to look back through the pages of Nature Structural & Molecular Biology and consider some of the year’s highlights.
The mitochondrial translocase complex TIM23 targets several hundreds of proteins to their location in the mitochondrial matrix or inner membrane. Recent studies provide important structural and mechanistic insights into the actions of the protein-import machinery in mitochondria.
Here the authors characterize the sequence-specific effect of an anticancer compound on mRNA cleavage, providing insights into the mechanism of mRNA 3′ processing.
Here, the authors show how binding of talin and kindlin to the β-integrin cytoplasmic tail increases talin and decreases kindlin affinity toward it, providing insights into mechanisms of integrin activation.
Using cryo-EM, Schmidt, Schulz, et al. solve the structure of the iron nitrogenase complex, which shows a unique architecture of alternative nitrogenases and suggests the G subunit to be involved in substrate channeling, stabilization of the cofactor and determining specificty among nitrogenase components.
The study presents a high-resolution structure of the retriever complex and a model of the retriever–CCC assembly, providing a mechanistic framework for studying how retriever facilitates endosomal recycling of diverse membrane proteins.
The androgen receptor forms nuclear condensates associated with gene transcription. Investigating the molecular basis of condensate formation led us to discover an approach for optimizing small molecules that inhibit the receptor in a currently untreatable form of prostate cancer.
The formation of the 2′–5′ lariat bond during branching is the critical first step in RNA splicing. A structure of a group II intron reveals a conserved base triple responsible for positioning the adenosine nucleophile to attack the 5′ splice site.
Here, cryo-electron microscopy structures of sodium–glucose cotransporter 2, which is responsible for sugar reabsorption in the kidney and is a target for the treatment of type 2 diabetes, reveal a potential mechanism for cellular sugar uptake.
Here, the authors show that the complete set of the Atg8–E1–E2–E3 conjugation machinery forms an interaction web through multivalent weak interactions, which mediates membrane shaping observed during autophagosome formation.
Here, the authors describe 3D hubs as regulatory subunits of gene expression in the three essential lineages of embryogenesis. They develop a computational model that can predict novel enhancers and they validate such enhancers in the context of specific lineages.
Transcription factors are rich in intrinsic disorder and therefore hard to drug. The authors improve an experimental drug for castration-resistant prostate cancer by learning how the activation domain of the androgen receptor activates transcription.
In this Review, the authors discuss the various ways that alternative splicing sculpts the landscape of protein interactions with their partners, essentially all types of biomolecules, and the implications of alternative interactions at the molecular, cellular and disease level.
We describe how transcription start site (TSS) choice of thousands of genes results in transcript isoforms with potential for distinct post-transcriptional regulation affecting translation and cell behavior. We show that dynamic switching between initiation sites defines cancer proliferation, differentiation and treatment response, indicating start site determination as a potential diagnostic tool.
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.
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.