Mechanism of action articles within Nature Communications

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  • Article
    | Open Access

    Guaianolides are pharmaceutically interesting molecules. Here, the authors isolate the enzyme kauniolide synthase from feverfew, show that it converts constunolide into a guaianolide via an unusual mechanism of action, and reconstruct the full kauniolide biosynthesis pathway in host organisms.

    • Qing Liu
    • , Arman Beyraghdar Kashkooli
    •  & Harro Bouwmeester

  • Article
    | Open Access

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor. Here the authors provide insights into PPARγ activation by combining fluorine (19F) NMR and molecular dynamics simulations to characterize the nuclear receptor conformational ensemble in solution and the response of this ensemble to ligand and coregulatory peptide binding.

    • Ian M. Chrisman
    • , Michelle D. Nemetchek
    •  & Travis S. Hughes

  • Article
    | Open Access

    Arrestins terminate signaling from GPCRs, but several lines of evidence suggest that they are also able to transduce signals independently of G proteins. Here, the authors systematically ablate G proteins in cell lines, and show that arrestins are unable to act as genuine signal initiators.

    • Manuel Grundmann
    • , Nicole Merten
    •  & Evi Kostenis

  • Article
    | Open Access

    The antibiotic vancomycin inhibits bacterial cell wall synthesis by binding to a membrane-associated precursor. Here, Blaskovich et al. synthesize vancomycin derivatives containing lipophilic peptide moieties that enhance membrane affinity and in vivo activities against glycopeptide-resistant strains.

    • Mark A. T. Blaskovich
    • , Karl A. Hansford
    •  & Matthew A. Cooper

  • Article
    | Open Access

    Several families of natural compounds target core components of the pre-mRNA splicing machinery and display anti-tumor activity. Here the authors show that particular sequence features can be linked to drug response, and that drugs with very similar chemical structures display substantially different effects on splicing regulation.

    • Luisa Vigevani
    • , André Gohr
    •  & Juan Valcárcel

  • Article
    | Open Access

    β1 and β2 adrenergic receptors (ARs) are the predominant G protein-coupled receptor subtypes expressed in mammalian hearts. Here the authors describe a signaling mechanism where the biased agonist carvedilol converts β1AR from a classical Gαs-coupled to a Gαi-coupled receptor to mediate β-arrestin-dependent signaling.

    • Jialu Wang
    • , Kenji Hanada
    •  & Howard A. Rockman

  • Article
    | Open Access

    Leishmaniasis is a parasitic disease transmitted by the bite of infected sand flies. Here the authors describe an atomic resolution cryo-EM structure of the Leishmania ribosome in complex with the recently approved drug paromomycin (PAR) and highlight conserved elements in the drug binding pocket that mediate PAR deleterious effects on the parasite.

    • Moran Shalev-Benami
    • , Yan Zhang
    •  & Georgios Skiniotis

  • Article
    | Open Access

    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.

    • Gabriela E. Davey
    • , Zenita Adhireksan
    •  & Curt A. Davey

  • Article
    | Open Access

    The mechanisms behind the antibacterial activity of the natural product carolacton are unknown. Here, the authors show that carolacton is a potent inhibitor of FolD/MTHFD enzymes (involved in folate-dependent C1 metabolism in bacteria and humans) and inhibits the growth of cancer cell lines

    • Chengzhang Fu
    • , Asfandyar Sikandar
    •  & Rolf Müller

  • Article
    | Open Access

    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.

    • Zenita Adhireksan
    • , Giulia Palermo
    •  & Curt A. Davey

  • Article
    | Open Access

    Omalizumab is an antibody against IgE that is used to treat patients with asthma and chronic idiopathic urticaria. Here, the authors report the structure of omalizumab in complex with an IgE fragment and develop an approach to exchange rather than deplete IgE on human basophils to block their activation.

    • Luke F. Pennington
    • , Svetlana Tarchevskaya
    •  & Theodore S. Jardetzky

  • Article |

    Berberine is contained in some plant-derived medicines and is known to have anti-diabetic effects. Here the authors show that berberine activates thermogenesis in white and brown adipose tissues, thereby increasing organismal energy expenditure and limiting weight gain in genetically obese mice.

    • Zhiguo Zhang
    • , Huizhi Zhang
    •  & Guang Ning

  • Article |

    The mechanism by which the common antibiotic streptomycin enters bacterial cells is unclear. Here, Iscla et al.show that streptomycin alters the activity of the bacterial mechanosensitive ion channel, MscL, inducing potassium efflux, and suggest that this channel may provide a route for cell entry.

    • Irene Iscla
    • , Robin Wray
    •  & Paul Blount

  • Article |

    Following myocardial infarction, patients are at risk for reperfusion-induced ventricular fibrillation, a life-threatening condition. Here, Liang et al. show that the known ventricular fibrillation preventive effects of carbon monoxide are mediated through the inhibition of a subset of inward-rectifying potassium channels.

    • Shenghui Liang
    • , Quanyi Wang
    •  & Yuchun Gu

  • Article |

    Overexpression of a drug’s molecular target increases drug resistance in some cases. Here the authors show that overexpressing antibiotic targets in Escherichia colican cause positive and negative changes in drug resistance, depending on whether the drug induces harmful reactions involving its target.

    • Adam C. Palmer
    •  & Roy Kishony

  • Article |

    Opioid analgesic drugs act at opioid receptors to exert analgesic effects, but they also exert adverse side effects. In this study, the authors show that the TREK-1 potassium channel is responsible for mediating the analgesic effects of morphine but not the adverse side effects.

    • Maïly Devilliers
    • , Jérôme Busserolles
    •  & Alain Eschalier

  • Article |

    As drug-resistant strains of Mycobacterium tuberculosis continue to emerge, antitubercular drugs with novel mechanisms of action are in high demand. Here, the authors show that ebselen is an inhibitor of M. tuberculosisantigen 85 and reveal the mechanism of inhibition.

    • Lorenza Favrot
    • , Anna E. Grzegorzewicz
    •  & Donald R. Ronning

  • Article
    | Open Access

    Tuberous sclerosis complex is an autosomal dominant cognitive disorder caused by mutations affecting TSCgenes. Sato and colleagues examine tuberous sclerosis complex mutant mice and find that the behavioural and anatomical abnormalities can be reversed by inhibiting rapamycin-sensitive signalling pathways, even in adulthood.

    • Atsushi Sato
    • , Shinya Kasai
    •  & Masashi Mizuguchi

  • Article |

    The iron–sulphur enzyme IspH catalyses the final step of the methylerythritol phosphate isoprenoid biosynthesis pathway. Spanet al. report that IspH can hydrate acetylenes to aldehydes and ketones, in addition to its role as a 2H+/2e−reductase.

    • Ingrid Span
    • , Ke Wang
    •  & Michael Groll

  • Article
    | Open Access

    Candidate anti-tuberculosis drugs are often identified in whole-cell screens. Here, Petheet al. show that inappropriate carbon-source selection can lead to the identification of compounds devoid of efficacy in vivo, underlining the importance of developing predictive in vitroscreens.

    • Kevin Pethe
    • , Patricia C. Sequeira
    •  & Thomas Dick

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