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    • Grant Miura
    Research Highlight
  • Developing inhibitors for SH2 domains is challenging due to their shallow pockets and highly charged ligands. Structure-guided drug design has enabled the discovery of a cell-permeable covalent inhibitor of the SOCS2 SH2 domain, a key regulator of cytokine signaling pathways.

    • Oliver Hantschel
    News & Views
  • O-linked N-acetylglucosamine (O-GlcNAc) is an endogenous form of glycosylation that alters the structure of α-synuclein amyloid fibrils and attenuates their pathogenetic properties. The modified fibrils have a significantly reduced ability to seed the aggregation of endogenous α-synuclein in cultured neurons and in mice brains in vivo, which results in reduced pathology.

    Research Briefing
  • NinaB is an isomerooxygenase that generates visual chromophore (11-cis-retinal) from carotenoid substrates. Here Solano et al. reveal the structural basis for NinaB isomerase activity, providing new insights into the evolution of visual chromophore synthesis by carotenoid cleavage enzymes.

    • Yasmeen J. Solano
    • Michael P. Everett
    • Philip D. Kiser
    ArticleOpen Access
  • BURP-domain proteins are an unexplored family of plant-specific, copper-dependent peptide cyclases. Here the authors show that a BURP-domain protein has a particular protein fold, investigate its mechanism and provide evidence for intramolecular modification in RiPP biosynthesis.

    • Lisa S. Mydy
    • Jordan Hungerford
    • Roland D. Kersten
  • Nonribosomal peptide synthetases produce diverse natural products, including many valuable therapeutics. Although the condensation domains that catalyze peptide bond formation in these multifunctional enzymes have been difficult to engineer, a yeast display system that was developed to screen millions of variants now enables efficient reprogramming of synthetase substrate specificity.

    Research Briefing
  • Transporters and channels have strong potential as drug targets, but drug discovery targeting these membrane-embedded molecules is challenging. Fragment-based ligand discovery combined with chemical proteomics offers a promising solution to the search for inhibitors of solute transporter family members.

    • Noriko Toyama-Sorimachi
    News & Views
  • α-Synuclein and tau can form multiple amyloid structures or strains that are associated with different neurodegenerative diseases, suggesting a strain–toxicity relationship. Now, it has been shown that O-GlcNAc modification of α-synuclein results in the formation of an amyloid strain that is largely nonpathogenic in vivo, supporting structure-dependent toxicity and another protective role for O-GlcNAc.

    • Aaron T. Balana
    • Anne-Laure Mahul-Mellier
    • Matthew R. Pratt
    ArticleOpen Access
  • Sulfated compounds produced collaboratively by the microbiome and the host have important biological functions. This Review highlights the production of select sulfated carbohydrates, amino acid derivatives and steroidal metabolites and discusses their influence on health. The Review also explore potential roles of sulfated molecules in disease detection, prevention and treatment.

    • Gabriel D. D’Agostino
    • Snehal N. Chaudhari
    • A. Sloan Devlin
    Review Article
  • Macromolecules can undergo liquid–liquid phase separation to form condensates that have critical roles in biological functions and dysfunctions. A new study demonstrates that differences in micropolarity between components is a prime determinant of the multiphasic architecture of biomolecular condensates.

    • My Diem Quan
    • Josephine C. Ferreon
    • Allan Chris M. Ferreon
    News & Views
  • Half a century after its discovery, platelet-activating factor (PAF) is now recognized as a ferroptosis-activating phospholipid that contributes to tubule cell damage and nephron loss in acute kidney injury.

    • Jiashuo Zheng
    • Bettina Proneth
    News & Views
  • Antigen reorientation via oligoD, a label-free, alum-based technique, guides immunofocused, broadly reactive antibody responses.

    • James A. Ferguson
    • Julianna Han
    • Andrew B. Ward
    News & Views
  • SUGAR-TARGET is a modular platform for the homogeneous synthesis of enzymes with controlled N-linked glycosylation using a one-step immobilization/purification method.

    • Elli Makrydaki
    • Roberto Donini
    • Cleo Kontoravdi
    ArticleOpen Access
  • Developing therapeutic agents that target the peptidylarginine deiminase PAD4 requires better understanding of the function of the enzyme. Isozyme-selective antibodies that alter PAD4 activity have been identified recently, revealing unique modes of action.

    • Masaki Unno
    News & Views