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The Drosophila tumour necrosis factor (TNF) system comprises a single ligand Eiger (Egr) and two receptors. The structure of Egr in complex with the extracellular domain of the receptor Grindelwald and accompanying data suggest that distinct affinities of TNF ligand for its receptors mediate non-redundant functions.

Ruthenium-cymene-based compounds are investigated as potential anticancer drugs. Here, Adhireksan et al.study two ruthenium-containing compounds with varying cytotoxicity and show that differences in ligand structure may explain their activity and binding to different subcellular targets.

Krebs and colleagues identify multiple mAbs that recognize either the RBD or the NTD of SARS-CoV-2 spike protein that have potent cross-neutralizing activities against variants of concern. Combinatorial mAb cocktails have complementary effects on viral neutralization and Fc effector functions and can protect against SARS-CoV-2 escape mutants.

Histone H2A–H2B dimers in nucleosomes contain an acidic patch, a highly electronegative cleft. Here, the authors characterize a family of binuclear ruthenium compounds that selectively target the acidic patch, generating intra-nucleosomal H2A-H2B cross-links as well as inter-nucleosomal cross-links.

Allostery and drug-drug synergism can yield potential novel therapies with existing molecules. Here, the authors provide evidence that two unrelated drugs have increased cytotoxicity in cancer cells, which coincides with increased formation of chromatin adducts.

In meso crystallization of membrane proteins is limited to proteins with small extracellular domains (ECDs). Here, authors combine monoacylglycerols and phospholipids to design stable ultra-swollen bicontinuous cubic phases that allow in meso crystallization of proteins with large ECDs.

Nocturnin is a rhythmically expressed protein that regulates metabolism under the control of circadian clock proposed to function through the deadenylation of metabolic enzyme mRNAs. Here the authors show that Nocturnin and its fly homolog Curled catalyze the removal of 2′-phosphate from NADP⁺ and NADPH, providing a direct link to metabolic regulation.

Simonetti et al. uncover an endosomal SNX–BAR sorting complex, ESCPE-1, that coordinates sequence-dependent cargo recognition with the formation of tubulo-vesicular transport carriers for endosomal export.

Malaria parasites reside in vacuoles during intracellular infection of erythrocytes and export many proteins into the host cell, a process that is essential for the virulence and viability of Plasmodium. Whereas transport across the parasite membrane is known to rely on the secretory pathway, the transporter responsible for the translocation of proteins across the vacuole membrane is now identified.

Host cell invasion by Toxoplasma gondii depends on the heavily phosphorylated RON complex, but the relevance and regulation of these modifications are not understood. Here, the authors identify the kinase RON13 as a key virulence factor, determine its structure and show that it phosphorylates the RON complex.

Bacteria use alternative sigma factors to direct transcription initiation from new sets of gene promoters in response to environmental stress. Complementary structural and biochemical analyses now reveal a new promoter-recognition mechanism that is the basis for the altered promoter specificity conferred by stress-responsive sigma factors.

Ethanol activates G protein-gated inwardly rectifying K⁺ (GIRK) channels, but it is unclear how. This study identifies an alcohol-binding pocket located in the cytoplasmic domains of GIRK2. A leucine residue in this pocket was crucial for GIRK2 activation by alcohols, but was not involved in the alcohol inhibition of related, but constitutively active, K⁺ channels.

Endonuclease V can initiate the repair of deaminated purine bases by recognizing them and hydrolyzing the second phosphodiester bond on their 3′ side. Now the crystal structures of endonuclease V in complex with its substrate and its product reveal a wedge motif acting as a minor groove–damage sensor and a pocket to recognize the lesion; the enzyme remains tightly bound to the 5′ phosphate product, perhaps to hand it over to downstream repair factors.

A new type of fungal lytic polysaccharide monooxygenase (LPMO) catalyzes the oxidative degradation of xylan components of cellulosic biomass and offers potential in wood biorefining.

Trypanosoma brucei inosine-5′-monophosphate dehydrogenase (IMPDH) is an enzyme in the guanine nucleotide biosynthesis pathway and of interest as a drug target. Here the authors present the 2.8 Å room temperature structure of TbIMPDH determined by utilizing X-ray free-electron laser radiation and crystals that were grown in insect cells and find that ATP and GMP are bound at the canonical sites of the Bateman domains.

Here, the X-ray crystal structure of the β₁ adrenergic receptor, a G-protein-coupled receptor, bound to four small molecules that either act as full agonists or partial agonists is solved. The structures show that agonist binding induces a contraction of the catecholamine-binding pocket relative to the antagonist-bound receptor. This work reveals the pharmacological differences between different ligand classes, which should facilitate the structure-based design of new drugs with predictable efficacies.

Using experiments in organoids and in vivo in mice, the authors show that Apc-mutant cells act as supercompetitors to initiate the formation of adenomas.

On the basis of new mechanistic studies of a mutant form of the apolipoprotein apoC-III that protects against coronary heart disease, Khetarpal et al. have developed therapeutic apoC-III-targeting monoclonal antibodies that lower circulating apoC-III protein and triglyceride levels in mice.

Rad50 is an ABC-type ATPase that forms a complex with the nuclease Mre11 and plays an essential role in the signaling and repair of DNA damage. Now crystal structures and SAXS analyses, along with functional assays, reveal how Rad50 transmits information between the ATPase and Mre11-binding sites, and the mechanism uncovered may be general to other ABC ATPases.

In a new study including 200 families who experienced perinatal death, adding genomic analyses to standard autopsies improved the identification of underlying pathogenic causes and informed genetic counseling.

Biomass combustion smoke transported from Africa accounts for about 60% of black carbon concentrations in the central Amazon during the rainy season, according to long-term measurements of refractory black carbon in 2019 and 2020