Chemical biology

  • Article
    | Open Access

    The herbivorous horseradish flea beetle sequesters plant toxins to defend against predators. Here the authors identify glucosinolate transporters expressed in the beetle Malpighian tubules and provide evidence that these reabsorb glucosinolates from the tubule lumen to prevent their loss by excretion.

    • Zhi-Ling Yang
    • , Hussam Hassan Nour-Eldin
    •  & Franziska Beran
  • Article
    | Open Access

    It is challenging to develop DNA probes that allow staining of both organelle and nuclear DNA, are compatible with super resolution imaging and avoid UV-light photo-excitation. The authors overcome these issues with N-aryl pyrido cyanine derivatives showing high DNA specificity and membrane permeability.

    • Kakishi Uno
    • , Nagisa Sugimoto
    •  & Yoshikatsu Sato
  • Article
    | Open Access

    Activation of cullin-RING ligases can be inhibited by targeting DCN1, but selective DCN1 inhibitors with in vivo activity are lacking. Here, the authors develop covalent DCN1 inhibitors that selectively and potently inhibit cullin-3 activation and downstream functions in cells and in mice.

    • Haibin Zhou
    • , Jianfeng Lu
    •  & Shaomeng Wang
  • Article
    | Open Access

    Non-ribosomal peptide synthetases (NRPSs) are multi-modular enzymes assembling complex natural products. Here, the structures of a Thermobifida fusca NRPS condensation domain bound to the substrate-bearing peptidyl carrier protein (PCP) domain provide insight into the mechanisms of substrate selectivity and engagement within the catalytic pocket.

    • Thierry Izoré
    • , Y. T. Candace Ho
    •  & Max J. Cryle
  • Article
    | Open Access

    The ER chaperone BiP is critical for the unfolded protein response and tightly regulated through reversible AMPylation by FICD, but the structural basis is unknown. Here the authors use thiol-reactive nucleotide derivatives to stabilize the transient FICD:BiP complex and determine its crystal structure.

    • Joel Fauser
    • , Burak Gulen
    •  & Aymelt Itzen
  • Article
    | Open Access

    Metabolites can distinguish pathogenic from healthy cells, but they are hard to couple to current photosensitizers without altering their biological activity. Here the authors design a new family of photosensitizers that retain metabolite function to target pathogenic cells and ablate them by photodynamic therapy.

    • Sam Benson
    • , Fabio de Moliner
    •  & Marc Vendrell
  • Article
    | Open Access

    Current aptamer discovery approaches are unable to probe the complete space of possible sequences. Here, the authors use machine learning to facilitate the development of DNA aptamers with improved binding affinities, and truncate them without significantly compromising binding affinity.

    • Ali Bashir
    • , Qin Yang
    •  & B. Scott Ferguson
  • Article
    | Open Access

    The detailed mechanisms of action of bactericidal antibiotics remain unclear. Here, Wong et al. show that these antibiotics induce cytoplasmic condensation through membrane damage and outflow of cytoplasmic contents, as well as accumulation of reactive metabolic by-products and lipid peroxidation, as part of their lethality.

    • Felix Wong
    • , Jonathan M. Stokes
    •  & James J. Collins
  • Article
    | Open Access

    Methods for selective modification of the N-terminus of proteins are of high interest, but mostly require specific amino acid residues. Here, the authors report a selective and fast method for N-terminal modification of proteins based on quinone-mediated oxidation of the alpha-amine to aldehyde or ketone, and apply it to diverse proteins.

    • Siyao Wang
    • , Qingqing Zhou
    •  & Ping Wang
  • Article
    | Open Access

    Arginine addiction induced by argininosuccinate synthase (ASSN1) deficiency has been exploited to treat ASS1-deficient cancers. Here, the authors show an alternative therapeutic approach where ASS1 activity is increased by the pesticide spinosyn A and is shown to inhibit breast cancer cell proliferation.

    • Zizheng Zou
    • , Xiyuan Hu
    •  & Zhiyong Luo
  • Article
    | Open Access

    P450 oxidoreductase (POR) selectively activates numerous cytochromes P450 (CYP), crucial for metabolism of drugs, steroids and xenobiotics and natural product biosynthesis. Here, the authors identify ligands that bind POR and bias its specificity towards CYP redox partners, activating distinct metabolic cascades in cells.

    • Simon Bo Jensen
    • , Sara Thodberg
    •  & Nikos S. Hatzakis
  • Article
    | Open Access

    Inhibition of the lipid peroxidase GPX4 promotes ferroptotic cell death. Here, the authors identify a complementary approach using conjugated linolenic fatty acids that trigger lipid peroxidation and ferroptosis via ACSL1, DGAT1/2, and neutral lipids.

    • Alexander Beatty
    • , Tanu Singh
    •  & Jeffrey R. Peterson
  • Article
    | Open Access

    Engineering efforts have focused on acyltransferase (AT) domains of modular polyketide synthases (PKSs) to site-selectively modify the resulting polyketides, but critical AT residues involved in substrate selection have not been fully elucidated. Here, the authors use molecular dynamics to pinpoint mutations that impact AT domain selectivity and exchange structural motifs to obtain chimeric PKS modules with expanded substrate specificity.

    • Edward Kalkreuter
    • , Kyle S. Bingham
    •  & Gavin J. Williams
  • Article
    | Open Access

    Streptoseomycin is a potent antibiotic that contains a pentacyclic 5/14/10/6/6 ring system. Here, the authors report the enzymatic and non-enzymatic steps of the downstream modification of streptoseomycin biosynthesis and show a [6 + 4]-cycloaddition adduct as an unexpected biosynthetic intermediate.

    • Kai Biao Wang
    • , Wen Wang
    •  & Hui Ming Ge
  • Article
    | Open Access

    Human manganese superoxide dismutase (MnSOD) is an oxidoreductase that uses concerted proton and electron transfers to reduce the levels of superoxide radicals in mitochondria, but mechanistic insights into this process are limited. Here, the authors report neutron crystal structures of Mn3+SOD and Mn2+SOD, revealing changes in the protonation states of key residues in the enzyme active site during the redox cycle.

    • Jahaun Azadmanesh
    • , William E. Lutz
    •  & Gloria E. O. Borgstahl
  • Article
    | Open Access

    Natural products inspire the development of pseudo-natural products through combinations of fragments of compound classes that are chemically and biologically distinct. Here, the authors report a library of 244 pseudo-natural products, evaluate them in the cell painting essays and identify the phenotypic role of individual fragments.

    • Michael Grigalunas
    • , Annina Burhop
    •  & Herbert Waldmann
  • Article
    | Open Access

    Buried charged networks in proteins are often important for their biological functionality and are believed to destabilise the protein fold. Here, the authors combine computational design, MD simulations, biophysical experiments, NMR and X-ray crystallography to design and characterise artificial 4α-helical proteins with buried charged elements. They analyse their conformational landscapes and observe that the ion-pairs are stabilised by amphiphilic residues that electrostatically shield the charged motif, which increases structural stability.

    • Mona Baumgart
    • , Michael Röpke
    •  & Ville R. I. Kaila
  • Article
    | Open Access

    Aminoglycoside antibiotics target the ribosome and induce misreading, yet which translation errors induce bacterial cell death is unclear. Here authors use quantitative mass spectrometry and show that bactericidal aminoglycosides induce clusters of errors in full-length proteins in vivo with as many as four amino acid substitutions in a row.

    • Ingo Wohlgemuth
    • , Raffaella Garofalo
    •  & Marina V. Rodnina
  • Article
    | Open Access

    Here, the authors present DisCo (Disassembly of Condensates), a method that allows the fast, inducible, and specific disruption of tagged condensates in mammalian cells. DisCo uses chemical dimerizers to induce the recruitment of a ligand into condensates leading to condensate disassembly.

    • Carmen N. Hernández-Candia
    • , Sarah Pearce
    •  & Chandra L. Tucker
  • Article
    | Open Access

    The demethylase FTO was shown to remove on N6-methyladenosine (m6A) and N6, 2’-O-dimethyladenosine (m6Am) modifications on RNAs. Here the authors show that FTO impedes cancer stem cell-like abilities in colorectal cancer cells through its m6Am demethylase activity, not through internal m6A demethylase activity.

    • Sébastien Relier
    • , Julie Ripoll
    •  & Alexandre David
  • Article
    | Open Access

    The methods for investigation of DNA-binding proteins require site-selective chemical modifications to be introduced into oligonucleotides. Here, the authors report a chemo- and regioselective method for the modification of unpaired guanosines in single- and double-stranded oligonucleotides, based on Rh(I)-carbene catalysis.

    • Yang-Ha Lee
    • , Eunsoo Yu
    •  & Cheol-Min Park
  • Article
    | Open Access

    Bio-mimetic motion has been hard to achieve due to a lack of biocompatible conditions. Here, the authors report the creation of a liposome-stabilised aqueous PEG/dextran Pickering-like emulsion system with motion induced by the Marangoni effect and characterised by negative chemotaxis.

    • Shaobin Zhang
    • , Claudia Contini
    •  & Oscar Ces
  • Article
    | Open Access

    Reveromycin A (RM-A) selectively inhibits eukaryotic cytoplasmic isoleucyltRNA synthetase (IleRS). Herein, the authors show that RM-A molecule occupies the tRNAIle binding site of Saccharomyces cerevisiae IleRS, and that RM-A cooperates with isoleucine or isoleucyl-adenylate for IleRS binding.

    • Bingyi Chen
    • , Siting Luo
    •  & Huihao Zhou
  • Article
    | Open Access

    Iron is an essential plant nutrient that is poorly bioavailable in alkaline soils, resulting in reduced agricultural productivity. Here, the authors report the synthesis of stable and cheap iron-chelator, proline-2’-deoxymugineic acid (PDMA), and demonstrate its utility as potential fertilizer.

    • Motofumi Suzuki
    • , Atsumi Urabe
    •  & Kosuke Namba
  • Article
    | Open Access

    RaPID (Random non-standard Peptides Integrated Discovery) enables discovery of small macrocyclic peptides binding desired targets. Here, the authors propose lasso-grafting: the RaPID-derived peptides are implanted onto diverse proteins and maintain both the binding properties of the cyclic peptide and the host protein function.

    • Emiko Mihara
    • , Satoshi Watanabe
    •  & Junichi Takagi
  • Article
    | Open Access

    So far most of the de novo designed proteins are for single states only. Here, the authors present the de novo design and crystal structure determination of a coiled-coil peptide that assembles into multiple, distinct conformational states under the same conditions and further characterise its properties with biophysical experiments, NMR and MD simulations.

    • William M. Dawson
    • , Eric J. M. Lang
    •  & Derek N. Woolfson
  • Article
    | Open Access

    Survivin’s dual function as apoptosis inhibitor and regulator of cell proliferation is mediated via its interaction with the export receptor CRM1. Here authors report a strategy addressing its dimer interface overlapping with the nuclear export signal, the binding site of CRM1, with advanced supramolecular tweezers for lysine and arginine.

    • Annika Meiners
    • , Sandra Bäcker
    •  & Shirley K. Knauer
  • Article
    | Open Access

    The ability to dynamically control protein-protein interactions and localization of proteins is critical in synthetic biological systems. Here the authors develop a peptide-based molecular switch that regulates dimer formation and lipid membrane targeting via reversible phosphorylation.

    • Leon Harrington
    • , Jordan M. Fletcher
    •  & Petra Schwille
  • Article
    | Open Access

    Monitoring the activity of the processive motor protein kinesin-1 in live cells is currently difficult. Here the authors report the fluorogenic small molecule QPD-OTf, a kinesin-1 substrate that causes activity-dependent dye precipitation.

    • Simona Angerani
    • , Eric Lindberg
    •  & Nicolas Winssinger
  • Article
    | Open Access

    Rubromycin family of natural products belongs to aromatic polyketides with diverse bioactivities, but details of their biosynthesis are limited. Here, the authors report the complete in vitro reconstitution of enzymatic formation of the spiroketal moiety of rubromycin polyketides, driven by flavin-dependent enzymes, and characterize reaction intermediates.

    • Britta Frensch
    • , Thorsten Lechtenberg
    •  & Robin Teufel
  • Article
    | Open Access

    Trans-acyltransferase polyketide synthases are multimodular enzymes that synthesise diverse polyketides. Here, the authors present an algorithm for the global study of their diversity, showing exchange of conserved consecutive modules as a driver of diversification, and guiding the discovery of polyketides.

    • Eric J. N. Helfrich
    • , Reiko Ueoka
    •  & Marnix H. Medema
  • Article
    | Open Access

    Furanocembranoid-like natural products with the alkene-substituted furan scaffold display a range of biological activities, but are difficult to access. Here, the authors report a modular biomimetic strategy to synthesise diverse alkene-substituted furan-containing macrolactams via palladium-catalysed unactivated Csp3-H olefination.

    • Jiping Hao
    • , Xueying Guo
    •  & Weibo Yang
  • Article
    | Open Access

    2,5-Dihydroxypyridine dioxygenase NicX uses a mononuclear non-heme Fe(II) to catalyze the oxidative pyridine ring cleavage of the pollutant 2,5-hydroxypyridine. Here, the authors report crystal structures of NicX, identify residues involved in substrate stabilization and Fe(II) coordination, and propose the catalytic mechanism of NicX.

    • Gongquan Liu
    • , Yi-Lei Zhao
    •  & Ping Xu
  • Article
    | Open Access

    Glycolipids are glycoconjugates with important biological functions, but techniques for their analysis are deficient. Here, the authors report the use of cryogenic gas-phase infrared spectroscopy to investigate isomerism in a set of immunologically relevant glycolipids, and show that their structural features can be accurately resolved based on a narrow spectral fingerprint region.

    • Carla Kirschbaum
    • , Kim Greis
    •  & Kevin Pagel
  • Article
    | Open Access

    The connection between metal binding to proteins and availabilities of different metals in cells has been unclear. Here, the authors report a metalation-calculator that takes into account competition between metals and their variable accessibility, and thereby elucidate in vivo metal occupancies of three different proteins, CobW, YeiR and YjiA.

    • Tessa R. Young
    • , Maria Alessandra Martini
    •  & Nigel J. Robinson
  • Article
    | Open Access

    Direct cloning of biosynthetic gene clusters is difficult due to their size and repetitive nature. Here, the authors present CAPTURE, which uses Cas12a and in vivo Cre-lox recombination for efficient cloning of gene clusters up to 113 kb, and demonstrate how this method can be used for large-scale discovery of novel natural products.

    • Behnam Enghiad
    • , Chunshuai Huang
    •  & Huimin Zhao
  • Article
    | Open Access

    The BCL-2 family protein BAX functions to regulate mitochondria-driven cell death. Here the authors show that the drug Eltrombopag inhibits BAX and prevents apoptosis induced by cytotoxic stimuli.

    • Adam Z. Spitz
    • , Emmanouil Zacharioudakis
    •  & Evripidis Gavathiotis
  • Article
    | Open Access

    Active-site loops are important for catalytic properties of enzymes, but challenging to engineer due to their high flexibility and diversity. Here, the authors identify and engineer hot-spots in the loops of cumene dioxygenase, obtain variants with changed activity, regio- and enantioselectivity, and present a Linker In Loop Insertion approach for loop modification.

    • Peter M. Heinemann
    • , Daniel Armbruster
    •  & Bernhard Hauer
  • Article
    | Open Access

    Coiled-coil protein origami (CCPO) is a strategy for the design of polyhedral cage-shaped protein folds based on coiled-coil (CC) dimer-forming peptides. Here, the authors show that CCPO proteins fold in a multistep process governed by the spatial distance between CC modules in the primary sequence and subsequent folding intermediates, which enables the use of identical CC modules for the CCPO tetrahedron design.

    • Jana Aupič
    • , Žiga Strmšek
    •  & Roman Jerala
  • Article
    | Open Access

    Coiled-coil protein origami is a strategy for the de novo design of polypeptide nanostructures based on coiled-coil dimer forming peptides, where a single chain protein folds into a polyhedral cage. Here, the authors design a single-chain triangular bipyramid and also demonstrate that the bipyramid can be self-assembled as a heterodimeric complex, comprising pre-defined subunits.

    • Fabio Lapenta
    • , Jana Aupič
    •  & Roman Jerala
  • Article
    | Open Access

    Accurately predicting the secondary structure of non-coding RNAs can help unravel their function. Here the authors propose a method integrating thermodynamic information and deep learning to improve the robustness of RNA secondary structure prediction compared to several existing algorithms.

    • Kengo Sato
    • , Manato Akiyama
    •  & Yasubumi Sakakibara
  • Article
    | Open Access

    Hundreds of BRAF mutations have been identified in patients with cancer but currently approved drugs only target BRAF V600 mutants. Here, the authors develop a vemurafenib-based PROTAC that induces degradation of all classes of BRAF mutants without affecting wild-type RAF proteins.

    • Shanique Alabi
    • , Saul Jaime-Figueroa
    •  & Craig M. Crews
  • Article
    | Open Access

    Biosynthesis of the statin precursor lovastatin depends on the LovB–LovC megasynthase complex. Here, the authors present cryoEM structures of LovB–LovC and core LovB, providing structural insights into the catalytic cycle underlying lovastatin production.

    • Jialiang Wang
    • , Jingdan Liang
    •  & Zhijun Wang