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Mitochondrial ferredoxins FDX1 and FDX2 are assigned to specifically donate electrons to steroidogenesis, Fe–S protein biogenesis, heme a formation or lipoylation. The proteins’ functions can be swapped by mutually exchanging short peptide segments.
Glutamine synthetase is the only enzyme that synthesizes glutamine in mammals. In vivo metabolomics showed that glutamine synthetase utilizes methylamine to produce N5-methylglutamine, whose levels correlate with tumor burden in a β+catenin+mutant liver cancer model.
YcaO enzymes carry out diverse tailoring reactions of peptide-derived natural products, such as formation of rings and incorporation of sulfur, but YcaO enzymes also catalyze peptide proteolysis using adenosine 5′-triphosphosphate as a co-factor.
Base editor technology combined with a fluorescent reporter of DNA methyltransferase activity enable in situ mutational scanning of DNMT3A, revealing a requirement of DNA binding by the PWWP histone reader domain for full activity.
By designing a fluorescent protein with a well characterized non-native ensemble, which captures the structural modulation of a substrate by the Hsp70/DnaJ/NEF system, Tiwari et al. resolved the individual steps of the disaggregation unfolding mechanism of Hsp70.
Reactive nitrogen species can cause profound inhibition of α-ketoacid dehydrogenase complexes via covalent S-modifications of the E2 subunit’s catalytic lipoic arm. The enzymes’ substrate, CoA, can mediate targeted delivery of such modifications.
Tan et al. reveal that a class of lipids, 3-sulfogalactosyl diacylglycerols, decrease in the central nervous system with aging. 3-sulfogalactosyl diacylglycerols are present in the human brain and suppress inflammation suggesting these lipids may play a role in age-related diseases and inflammation.
Structure and mutagenesis of the colibactin-activating peptidase ClbP reveals a dimer with a substrate-binding transmembrane domain and a conserved polar network in its periplasmic domain that enforces selectivity for d-asparagine prodrug motifs.
A substrate-guided design strategy generated highly potent inhibitors of the biosynthesis of the genotoxin colibactin by human gut bacteria. These inhibitors also enable a generalizable approach for chemically guided natural product discovery.
The structure of fungal sterol receptor Upc2 reveals ligand specificity and mechanism of transcriptional activation contributing to azole resistance. A regulatory role of Hsp90 chaperone in ergosterol-dependent translocation of Upc2 was discovered.
A small molecule was developed that disrupted the lipid–SH2 domain interaction of the spleen tyrosine kinase (Syk), suppressed oncogenic activities in acute myeloid leukemia cell lines and was refractory to drug resistance.
Phase separation of androgen receptor underlies mutation-mediated antiandrogen resistance. A phenotypic screen enabled the discovery of ET516, which disrupts androgen receptor phase separation and effectively suppresses the growth of prostate cancer.
A precise adenine base editor variant, ABE9, was developed to generate single adenine transition at pathogenic homopolymeric adenine sites with minimal DNA/RNA off-target effects, suggesting promising potential for gene therapeutics.
Untargeted comparative metabolomics revealed serotonin biosynthesis and metabolism pathways in nonneuronal tissues that contribute to established serotonin-dependent phenotypes in C. elegans.
Aminoadamantane compounds, delivered to cells via binding to viroporin channels, induce S-nitrosylation of the ACE2 protein, inhibiting binding to SARS-CoV-2 spike protein and viral infection.
An INSPIRE platform for therapeutic regulators and sensors, based on split human domains binding physiological or clinically approved compounds, has been developed and demonstrated on several human proteins in a relevant ligand concentration range.
Cryo-EM structures of the mouse TRPV2 channel, combined with electrophysiology and simulations, reveal that endogenous cholesterol binds to the vanilloid binding pocket to inhibit this channel, while exogenous 2-APB binds to same pocket to open TRPV2.
Mukherjee et al. report that AcrIF24 is an Acr-Aca fusion protein that inhibits the Csy complex and suppresses transcription from the acrIF23–acrIF24 promoter, and they present cryo-EM structures to reveal the mechanism for both roles of AcrIF24.
DNA-templated compound library screening and structure-guided hit optimization resulted in the identification of selective macrocyclic inhibitors of cyclophilin isoforms CypD and CypE.