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The authors describe the structure of an adenylyl cyclase 5 and Gβγ complex, which potentially influences a neural signalling pathway modulating motor function. Mutations in the Gβγ binding site on AC5 are linked to heritable forms of dyskinesia.

The authors report the structures of human CHT1 in the outward-open, inward-occluded and inward-open states, reveal the mechanism of HC-3 inhibition and choline recognition and elucidate the regulatory role of the intracellular helix IH1.

Here the authors structurally characterize respiratory supercomplexes, revealing that, in addition to the known ‘canonical’ respirasome, mammalian mitochondria contain two novel respirasome types, one of which incorporates supercomplex assembly factor SCAF1.

Pregnancy loss is common in humans, but maternal genetic factors modulating its incidence are largely unknown. In a meta-analysis of genome-wide association studies, researchers identified a genetic variant that seems to increase risk of pregnancy loss by dysregulating meiotic recombination between homologous chromosomes during egg formation.

G protein-coupled receptors (GPCRs) with no known endogenous ligand are termed orphans. Deorphanization of a GPCR involves identifying the ligand, which can be a painstaking exercise. In this Comment, we discuss the challenges in the process, its role in drug discovery and alternative approaches to characterizing orphan GPCRs.

Phosphoinositide 3-kinase γ plays critical roles in neutrophil chemotaxis and cancer metastasis. Here, using cryo-EM and functional studies, the authors reveal how two molecules of a key activator, Gβγ, bind to and alter the conformation of the enzyme.

Cryo-electron microscopy of brain tissue from two individuals with Down syndrome showed amyloid-β (Aβ) and tau filaments identical to those found in individuals with sporadic or dominantly inherited Alzheimer disease (AD), but also two types of Aβ₄₀ filaments with distinct structures different from those previously reported in AD and cerebral amyloid angiopathy.

Here, using cryo-EM, authors reveal that amyloid-β and tau are identical in Alzheimer disease and Down syndrome. This has implications for assessing whether adults with Down syndrome could be included in Alzheimer disease clinical trials.

The identification of sodium and potassium currents as underlying action potential propagation, more than 70 years ago, opened a new avenue of research into the role of ion channels. In this Comment, we present our personal perspectives of the field, from the identification of Shaker as a potential potassium channel to the mechanistic insights available to us today.

Here, four cryo-EM structures of Mtb OppABCD reveal an assembly of a cluster C substrate-binding protein and its translocator, as well as the [4Fe–4S] cluster-regulated transport mechanism of oligopeptide permeases found in bacteria.

Precise protein synthesis is achieved by tRNA modifications. Here the authors revealed that modified cytidines in tRNA^Ile use their long side chains to make additional interactions with mRNA for stable tRNA binding on the ribosome.

Rybak and Gagnon elucidate the mechanism of AUG codon avoidance by the minor isoleucine tRNA in Escherichia coli. The lysidinylated C34 in the anticodon loop of tRNA^Ile weakens interactions with the mRNA and destabilizes the EF-Tu ternary complex.

Transcription of toxin–antitoxin modules is regulated by conditional cooperativity, where the toxin enables or disrupts antitoxin-driven repression. Here, the authors solve the structural basis for the conditional cooperativity of Salmonella TacAT3.

Cryo-EM studies reveal that RYBP–PRC1 uses two distinct interfaces for binding unmodified and H2Aub1-modified nucleosomes. These binding modes enable the complex to generate H2Aub1 chromatin domains by a read–write mechanism.

In addition to the usual dose of compelling science, our March issue features thoughtful reflections on the last 30 years from readers, as well as past and present editors. Perhaps influenced by these pieces or by our stunning cover — or maybe it is just the changing seasons — we are in an introspective mood this month.

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.

Examining artificial embryos (gastruloids), Merle et al. uncover precise gene organization and proportional growth, providing insights into fundamental principles of developmental processes in mammalian systems.