Chemical biology

  • Article
    | Open Access

    Antibiotic resistance in Staphylococcus aureus is associated with reduced neutrophil recruitment. Here, Payne et al. link formylated peptides, which act as chemoattractants for neutrophils, with the antibiotic vancomycin and show that these hybrid compounds improve clearance of S. aureus by neutrophils.

    • Jennifer A. E. Payne
    • , Julien Tailhades
    •  & Max J. Cryle
  • Article
    | Open Access

    Isoflavonoids are a class of industrially important plant natural products, but their low abundance and structural complexity limits their availability. Here, the authors engineer Saccharomyces cerevisiae metabolism to become a platform for efficient production of daidzein which is core chemical scaffold for isoflavonoid biosynthesis, and show its application for production of bioactive glucosides from glucose.

    • Quanli Liu
    • , Yi Liu
    •  & Jens Nielsen
  • Article
    | Open Access

    Changes in intracellular GTP levels are not considered as a regulatory event in RAC1 activation in live cells since total GTP levels are substantially higher than the RAC1 GTP dissociation constant determined in vitro. Here, the authors demonstrate that the availability of free GTP in live cells controls the activity of RAC1 and cell invasion.

    • Anna Bianchi-Smiraglia
    • , David W. Wolff
    •  & Mikhail A. Nikiforov
  • Article
    | Open Access

    RNA-protein interactions play critical roles in post-transcriptional gene regulation. Here the authors demonstrate pRBS-ID, an updated MS/MS-based method that combines the benefits of photoactivatable ribonucleosides and the chemical cleavage of RNA.

    • Jong Woo Bae
    • , Sangtae Kim
    •  & Jong-Seo Kim
  • Article
    | Open Access

    The directed evolution of antibodies yields important tools for research and therapy. Here the authors develop a periplasmic phage-assisted continuous evolution platform for improvement of protein-protein interactions in the disulfidecompatible E. coli periplasm.

    • Mary S. Morrison
    • , Tina Wang
    •  & David R. Liu
  • Article
    | Open Access

    Aberrant EGFR activation is commonly found in non-small cell lung cancer (NSCLC). Here the authors show that E3 ubiquitin ligase FBXL2 targets EGFR and EGFR tyrosine kinase inhibitor (TKI)-resistant mutants for proteasome-mediated degradation to inhibit EGFR-driven NSCLC growth and TKI resistance.

    • Mengmeng Niu
    • , Jing Xu
    •  & Zhi-Xiong Jim Xiao
  • Article
    | Open Access

    Iron-sulfur (FeS) proteins are involved in electron transfer and CO2 fixation. Here, the authors show that FeS clusters can form spontaneously in the presence of the amino acid cysteine, in conditions similar those expected in Hadean alkaline hydrothermal vents, suggesting a plausible mechanism of their emergence at the origin of life.

    • Sean F. Jordan
    • , Ioannis Ioannou
    •  & Nick Lane
  • Article
    | Open Access

    Application of adenine base editors (ABE) has been precluded by low activity. Here the authors show the generation of a human cell based ABE directional screening system and identification of ABE variant (NG-ABEmax-KR) exhibiting a significant increase in activity for human and mouse genome manipulation.

    • Junhao Fu
    • , Qing Li
    •  & Feng Gu
  • Article
    | Open Access

    Microbial evolution often involves transient phenotypes and sequential development of multiple mutations of unclear relevance. Here, the authors show that the evolution of non-growing E. coli cells can be driven by alterations in pyrimidine nucleoside levels associated with colony ageing and/or due to mutations in metabolic or regulatory genes.

    • Ida Lauritsen
    • , Pernille Ott Frendorf
    •  & Morten H. H. Nørholm
  • Article
    | Open Access

    Small-molecule responsive protein switches are crucial components to control synthetic cellular activities. Here, we present a computational protein design strategy to repurpose drug-inhibited protein-protein interactions into OFF- and ON-switches active in cells.

    • Sailan Shui
    • , Pablo Gainza
    •  & Bruno E. Correia
  • Article
    | Open Access

    The mechanism-of-action of many electrohilic drugs remains poorly understood. Here, the authors use a redox-targeting approach to elucidate the basis for the innate immune cell toxicity of dimethyl fumarate, showing that it modifies Keap1 to trigger mitochondrial-targeted neutrophil/macrophage apoptosis.

    • Jesse R. Poganik
    • , Kuan-Ting Huang
    •  & Yimon Aye
  • Article
    | Open Access

    Simultaneous detection of multiple analytes from a sample is currently difficult. Here the authors present protocell arrays in a customisable platform integrating cell-free expression with a polymer-based aqueous two-phase system; they use this for detection of chemically diverse targets from biofluids.

    • Yan Zhang
    • , Taisuke Kojima
    •  & Mark P. Styczynski
  • Article
    | Open Access

    In vitro protein folding can often result in aggregation and low yields. Here the authors use nanoscale exoshells to improve soluble yield, functional yield and specific activity of folded proteins.

    • Samira Sadeghi
    • , Siddharth Deshpande
    •  & Chester L. Drum
  • Article
    | Open Access

    Genetic code expansion strategies are limited to specific codons that can be reassigned to new amino acids. Here the authors show that quadruplet-decoding tRNAs (qtRNAs) can be rapidly discovered and evolved to decode new quadruplet codons, enabling four independent decoding events in a single protein in living cells.

    • Erika A. DeBenedictis
    • , Gavriela D. Carver
    •  & Ahmed H. Badran
  • Article
    | Open Access

    Enzymes installing an intact hydropersulfide (-SSH) group into natural products have so far not been identified. Here, the authors report the characterization of an S-adenosyl methionine-dependent hydropersulfide methyltransferase (GnmP) for guangnanmycin biosynthesis, and identification of three SH domains within several NRPS-PKS assembly lines as thiocysteine lyases.

    • Song Meng
    • , Andrew D. Steele
    •  & Ben Shen
  • Article
    | Open Access

    Humans are exposed to millions of chemicals but mass spectrometry (MS)-based targeted biomonitoring assays are usually limited to a few hundred known hazards. Here, the authors develop a workflow for MS-based untargeted exposome profiling of known and unidentified environmental chemicals.

    • Xin Hu
    • , Douglas I. Walker
    •  & Dean P. Jones
  • Article
    | Open Access

    KLF4, OCT4, SOX2 and MYC cooperate to reorganize chromatin during somatic cell reprogramming. Here the authors show that KLF4 forms a liquid-like biomolecular condensate that recruits OCT4 and SOX2, and that condensation of the isolated KLF4 DNA binding domain with DNA is enhanced by CpG methylation

    • Rajesh Sharma
    • , Kyoung-Jae Choi
    •  & Josephine C. Ferreon
  • Article
    | Open Access

    Epistasis plays an important role in the evolution of novel protein functions because it determines the mutational path a protein takes. Here, the authors combine functional, structural and biophysical analyses to characterize epistasis in a computationally redesigned ligand-inducible allosteric transcription factor and found that epistasis creates distinct biophysical and biological functional landscapes.

    • Kyle K. Nishikawa
    • , Nicholas Hoppe
    •  & Srivatsan Raman
  • Article
    | Open Access

    Faster, higher throughput antibody engineering methods are needed. Here the authors present CeVICA, a cell-free nanobody engineering platform using ribosome display and computational clustering analysis for in vitro selection; they use this to develop nanobodies against the RBD of SARS-CoV-2 spike protein.

    • Xun Chen
    • , Matteo Gentili
    •  & Aviv Regev
  • Article
    | Open Access

    Methyl salicylate ester is a plant metabolite involved in plant-insect and plant-plant interactions. Here, Yu et al. show that a nematode-trapping fungus has potential to produce a related compound, 6-methyl salicylate, which attracts its prey (nematodes) and modulates spore germination and trap formation in the fungus.

    • Xi Yu
    • , Xiaodi Hu
    •  & Reinhard Fischer
  • Article
    | Open Access

    Here, Broszeit et al. show that circulating A/H3N2 viruses have evolved binding specificity to α2,6-sialosides on extended LacNAc moieties and therefore cannot agglutinate erythrocytes. Applying glycan remodeling allows to install functional receptors on erythrocytes and promotes identification of newly circulating variants to facilitate vaccine design.

    • Frederik Broszeit
    • , Rosanne J. van Beek
    •  & Geert-Jan Boons
  • Article
    | Open Access

    Humans are exposed to many xenobiotic chemicals, but identification of low abundance xenobiotic exposures is limited by a lack of authentic standards for xenobiotic metabolites. Here the authors develop methods for enzymatic generation of diverse xenobiotic metabolites for use with high-resolution mass spectrometry for biology-based chemical identification.

    • Ken H. Liu
    • , Choon M. Lee
    •  & Dean P. Jones
  • Article
    | Open Access

    Borosins are ribosomally encoded and posttranslationally modified peptide (RiPP) natural products featuring amide-backbone α-N-methylation. Here, the authors report the discovery and characterization of type IV borosin ‘split’ pathways encoding distinct, separate α-N-methyltransferases and precursor peptide substrates.

    • Fredarla S. Miller
    • , Kathryn K. Crone
    •  & Michael F. Freeman
  • Article
    | Open Access

    Elucidating specific effects of protein kinase Akt isoforms remains challenging. Here, the authors establish an Akt isoform-dependent cellular model system and use it, together with X-ray crystallography and structure-based ligand design, to develop isoform-selective covalent-allosteric Akt inhibitors

    • Lena Quambusch
    • , Laura Depta
    •  & Daniel Rauh
  • Article
    | Open Access

    Here, the authors engineer microbial production of muscle titin fibers with highly desirable mechanical properties and provide structural analyses that explain the molecular mechanisms underlying high performance of this polymer with potential uses in biomedicine and textile industries, among others.

    • Christopher H. Bowen
    • , Cameron J. Sargent
    •  & Fuzhong Zhang
  • Article
    | Open Access

    Integration and communication of distinct chemical reaction networks is a biological strategy for controlling dynamics of hierarchical structures. Here, the authors report ATP-fuelled autonomous DNA nanotube assembly regulated by DNA strand displacement reactions, which are induced and controlled by an upstream enzyme reaction network of concurrent ATP-mediated ligation and restriction of DNA components.

    • Jie Deng
    •  & Andreas Walther
  • Article
    | Open Access

    Understanding the structure and dynamics of enzymes is important for a number of applications. Here, the authors report on the crystal structure of vanillic acid decarboxylase, and show how the dynamics of the UbiD superfamily enzymes relate to the covalent catalysis of aromatic (de)carboxylation.

    • Stephen A. Marshall
    • , Karl A. P. Payne
    •  & David Leys
  • Article
    | Open Access

    Cholesterol metabolism is involved in the progression of aggressive prostate cancer (PCa). Here the authors show that miR-205 downregulation promotes cholesterol synthesis and androgen receptor signalling in PCa through enhancing the expression of the rate-limiting enzyme of cholesterol synthesis, squalene epoxidase.

    • C. Kalogirou
    • , J. Linxweiler
    •  & A. Schulze
  • Article
    | Open Access

    Glycomics can uncover important molecular changes but measured glycans are highly interconnected and incompatible with common statistical methods, introducing pitfalls during analysis. Here, the authors develop an approach to identify glycan dependencies across samples to facilitate comparative glycomics.

    • Bokan Bao
    • , Benjamin P. Kellman
    •  & Nathan E. Lewis
  • Article
    | Open Access

    5-Hydroxymethylfurfural (HMF) can be transformed to a range of industrially useful derivatives, such as 2,5-diformylfuran (DFF), but the reactions needed for efficient industrial production are hindered by several issues. Here, the authors perform reaction and enzyme engineering resulting in a galactose oxidase variant with high activity towards HMF, improved oxygen binding and high productivity.

    • William R. Birmingham
    • , Asbjørn Toftgaard Pedersen
    •  & Nicholas J. Turner
  • Article
    | Open Access

    The only known animal polyketide-nonribosomal peptides, the nemamides, are biosynthesized by two megasynthetases in the canal-associated neurons (CANs) of C. elegans. Here, the authors map the biosynthetic roles of individual megasynthetase domains and identify additional enzymes in the CANs required for nemamide biosynthesis.

    • Likui Feng
    • , Matthew T. Gordon
    •  & Rebecca A. Butcher
  • Article
    | Open Access

    C-Glycosyl peptides/proteins are metabolically stable mimics of the native glycopeptides/proteins of great therapeutic potential, but their chemical synthesis is challenging. Here, the authors report a protocol for the synthesis of vinyl C-glycosyl amino acids and peptides, via a Ni-catalyzed reductive hydroglycosylation reaction of alkyne derivatives of amino acids and peptides with glycosyl bromides.

    • Yan-Hua Liu
    • , Yu-Nong Xia
    •  & Biao Yu
  • Article
    | Open Access

    Analogues of α-ketoglutarate are used in many cellular studies but assumptions are made about cellular uptake. Here, the authors show that esterified analogues rapidly hydrolyse in aqueous medium resulting in an analogue which can be quickly taken up by many cell lines, contrary to prevailing assumptions.

    • Seth J. Parker
    • , Joel Encarnación-Rosado
    •  & Alec C. Kimmelman
  • Article
    | Open Access

    Various strategies to assemble protein building blocks into one-, two- and three-dimensional hierarchical nanostructures were described, but controlling the transformation between those different assemblies is largely uninvestigated. Here, the authors describe a protein interface redesign strategy and use it for the self-assembly transformation of dimeric building blocks from hollow protein nanocage to filament, nanorod and nanoribbon.

    • Xiaorong Zhang
    • , Yu Liu
    •  & Guanghua Zhao
  • Article
    | Open Access

    Nicotinic acid adenine dinucleotide phosphate (NAADP) potent Ca2+ mobilizing second messenger which uniquely triggers Ca2+ release from acidic endolysosomal organelles. Here the authors identify Lsm12 as an NAADP receptor essential for NAADP-evoked Ca2+ release from lysosomes via NAADP binding on its Lsm domain.

    • Jiyuan Zhang
    • , Xin Guan
    •  & Jiusheng Yan
  • Article
    | Open Access

    Here, the authors show structural, biochemical, and functional insights into the discovery of epichaperome‐ directed chemical probes for use in central nervous system diseases. Probes emerging from this work have translated to human clinical studies in Alzheimer’s disease and cancer.

    • Alexander Bolaender
    • , Danuta Zatorska
    •  & Gabriela Chiosis
  • Article
    | Open Access

    While Ras is a promising target for cancer therapy, development of inhibitors targeting Ras signaling has proven challenging. Here, the authors report the discovery of Rasarfin, a small molecule from a phenotypic screen on G protein-coupled receptor (GPCR) endocytosis that acts as a dual Ras and ARF6 inhibitor.

    • Jenna Giubilaro
    • , Doris A. Schuetz
    •  & Stéphane A. Laporte
  • Article
    | Open Access

    This study describes a class of small molecule compounds that promote ABCA1-dependent cholesterol efflux via a non-transcriptional mechanism, the identification of the molecular target by a chemical biology approach, and the potential of these agents for the treatment of chronic kidney diseases and potentially other diseases where lipid accumulation drives disease progression.

    • Matthew B. Wright
    • , Javier Varona Santos
    •  & Alessia Fornoni