Mechanism of action

  • 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

    Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.

    • Yi Yang
    • , Adam Csakai
    •  & Hang Yin
  • Article
    | Open Access

    The intracellular compartment is a crowded environment. Here, the authors use molecular dynamics (MD) simulations to assess inhibitor binding to c-Src kinase and show how ligand binding pathways differ in crowded and dilute protein solutions, highlighting the role of c-Src Tyr82 sidechain.

    • Kento Kasahara
    • , Suyong Re
    •  & Yuji Sugita
  • Article
    | Open Access

    The membrane is an integral component of the G protein-coupled receptor signaling machinery. Here authors demonstrate that lipids regulate the signaling efficacy and selectivity of the ghrelin receptor GHSR through specific interactions and bulk effects and observe PIP2 and GM3 induced shifts of the conformational equilibrium of GHSR away from its inactive state.

    • Marjorie Damian
    • , Maxime Louet
    •  & Jean-Louis Banères
  • 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

    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

    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

    TNF can be inhibited by small molecules that stabilize the TNF trimer in an asymmetric conformation. Here, the authors develop a monoclonal antibody that selectively binds this inactive form of TNF, enabling both target engagement assessment and structural characterization of TNF binding to TNF receptor 1.

    • Daniel J. Lightwood
    • , Rebecca J. Munro
    •  & Alastair D. G. Lawson
  • Article
    | Open Access

    The drug-like compound PF846 and its derivatives inhibit the translation of specific mRNAs by the human ribosome. Here the authors show how PF846 arrests translation at the stop codon by slowing hydrolysis of the protein nascent chain at the ribosome P-site tRNA by eukaryotic release factor 1 (eRF1).

    • Wenfei Li
    • , Stacey Tsai-Lan Chang
    •  & Jamie H. D. Cate
  • Article
    | Open Access

    5-hydroxythalidomide is a primary thalidomide metabolite generated by the cytochrome P450 isozymes. The reported data, including crystal structure of the 5-hydroxythalidomide-mediated complex of CRBN with SALL4, elucidate how additional hydroxy group of the metabolite enhances the interaction of CRBN with the neosubstrate SALL4.

    • Hirotake Furihata
    • , Satoshi Yamanaka
    •  & Takuya Miyakawa
  • Article
    | Open Access

    Antibiotics targeting protein translation interact in hard-to-predict ways. Here, Kavčič et al. interpret these interactions in terms of translation bottlenecks, the kinetics of drug uptake and target binding, bacterial growth laws, and a model of queued traffic progression.

    • Bor Kavčič
    • , Gašper Tkačik
    •  & Tobias Bollenbach
  • Article
    | Open Access

    Small molecule stabilizers of protein–protein interactions hold great therapeutic potential. Based on virtual screening and molecular docking, the authors here develop a strategy to evolve weak, promiscuous inhibitors of 14-3-3 interactions into selective stabilizers of the 14-3-3/ChREBP complex.

    • Eline Sijbesma
    • , Emira Visser
    •  & Christian Ottmann
  • Article
    | Open Access

    Upon transition to stationary phase or upon stress, bacteria limit protein synthesis through small inhibitory proteins that bind the ribosome. Here the authors decipher the interaction mode of the bacterial ribosome silencing factor (RsfS) at atomic details to provide an in depth view of how it shutdowns ribosomes.

    • Iskander Khusainov
    • , Bulat Fatkhullin
    •  & Marat Yusupov
  • Article
    | Open Access

    Bacillus thuringiensis israelensis (Bti) produces the naturally-crystalline proteinaceous toxin Cyt1Aa that is toxic to mosquito larvae. Here the authors grow recombinant nanocrystals of the Cyt1Aa protoxin in vivo and use serial femtosecond crystallography to determine its structure at different redox and pH conditions and by combining their structural data with further biochemical, toxicological and biophysical analyses provide mechanistic insights into the Cyt1Aa bioactivation cascade.

    • Guillaume Tetreau
    • , Anne-Sophie Banneville
    •  & Jacques-Philippe Colletier
  • Article
    | Open Access

    Formylpeptide receptors (FPRs) are a class of chemotactic G protein-coupled receptors (GPCRs) that recognize pathogen- and host-derived formylpeptides. Here the authors report the 3.17 Å cryo-EM structure of the human FPR2-Gi signaling complex with a bound peptide agonist and in combination with computational docking and MD simulations provide mechanistic insights into formylpeptide recognition by FPRs.

    • Youwen Zhuang
    • , Heng Liu
    •  & Cheng Zhang
  • Article
    | Open Access

    The biology of Alzheimer’s disease (AD) remains unknown. We propose AD is a protein connectivity-based dysfunction disorder whereby a switch of the chaperome into epichaperomes rewires proteome-wide connectivity, leading to brain circuitry malfunction that can be corrected by novel therapeutics.

    • Maria Carmen Inda
    • , Suhasini Joshi
    •  & Gabriela Chiosis
  • Article
    | Open Access

    The ERK signalling pathway is activated in many cancers, however ERK1 and ERK2 are difficult to target pharmacologically. Here, the authors identify a small molecule inhibitor that binds covalently to the D-recruitment site of ERK and induces cell death and reduces tumour growth in mice.

    • Tamer S. Kaoud
    • , William H. Johnson
    •  & Kevin N. Dalby
  • Article
    | Open Access

    Osh6p and Osh7p are yeast lipid transfer proteins (LTPs) that must transiently interact with membranes but how they escape from the electrostatic attraction of the plasma membrane is unclear. Here authors show that Osh6p reduces its avidity for anionic membranes once it captures PS or PI4P, due to a molecular lid closing its lipid-binding pocket.

    • Nicolas-Frédéric Lipp
    • , Romain Gautier
    •  & Guillaume Drin
  • Article
    | Open Access

    Curaxins are a recently discovered class of anti-cancer agents that disturbs DNA/histone interactions within. Here the authors provide evidence that curaxins affect the spatial genome organization and compromise enhancer-promoter communication necessary for expression of several oncogenes, including MYC.

    • Omar L. Kantidze
    • , Artem V. Luzhin
    •  & Sergey V. Razin
  • Article
    | Open Access

    PROTACs enable targeted protein degradation by recruiting an E3 ligase to a specific substrate but the determinants of selectivity are not fully understood. Here, the authors show that varying the linker between warhead and E3 ligand and the orientation of the E3 ligase allow tuning PROTAC selectivity toward different p38 isoforms.

    • Blake E. Smith
    • , Stephen L. Wang
    •  & Craig M. Crews
  • 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