Mechanism of action articles within Nature

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  • Article
    | Open Access

    Studies using genetic screening, biophysical characterization and structural reconstitution elucidate the mechanism of action and enable rational design of a new class of functional compounds that glue target proteins to E3 ligases via intramolecularly bridging two domains to enhance intrinsic protein–protein interactions and promote target ubiquitination and degradation.

    • Oliver Hsia
    • , Matthias Hinterndorfer
    •  & Alessio Ciulli

  • Article
    | Open Access

    A mechanism of lipid transport inhibition has been identified for a class of peptide antibiotics effective against resistant Acinetobacter strains, which may have applications in the inhibition of other Gram-negative pathogens.

    • Karanbir S. Pahil
    • , Morgan S. A. Gilman
    •  & Daniel Kahne

  • Article
    | Open Access

    Biochemical and molecular dynamics studies show that the third intracellular loop of G protein-coupled receptors autoregulates the receptor activity and tunes the signalling specificity by controlling access to the G protein-binding site.

    • Fredrik Sadler
    • , Ning Ma
    •  & Sivaraj Sivaramakrishnan

  • Article |

    Binding of the small molecule BI-3802 to the oncogenic transcription factor B cell lymphoma 6 (BCL6) induces polymerization of BCL6, leading to its ubiquitination by SIAH1 and proteasomal degradation.

    • Mikołaj Słabicki
    • , Hojong Yoon
    •  & Benjamin L. Ebert

  • Letter |

    The development of selective ubiquitin-specific protease-7 (USP7) inhibitors GNE-6640 and GNE-6776, which induce tumour cell death and reveal differential kinetics of Lys-48 and Lys-63-linked ubiquitin chain depolymerization by USP7.

    • Lorna Kategaya
    • , Paola Di Lello
    •  & Ingrid E. Wertz

  • Article |

    This paper reports the identification of a new cereblon-modulating agent, CC-885, which targets the translation termination factor GSPT1 and demonstrates anti-tumour activity in patient-derived tumour cells; the crystal structure of the cereblon–DDB1–GSPT1–CC-885 complex reveals a common motif for cereblon-substrate recruitment.

    • Mary E. Matyskiela
    • , Gang Lu
    •  & Philip P. Chamberlain

  • Letter |

    The drug daclatasvir (DCV), which inhibits the hepatitis C virus (HCV) non-structural protein 5A (NS5A), can successfully reduce viral load in patients; here, a combination of DCV and an NS5A analogue is shown to enhance DCV potency on multiple genotypes and overcome resistance in vitro and in a mouse model.

    • Jin-Hua Sun
    • , Donald R. O’Boyle II
    •  & Min Gao

  • Article |

    Lenalidomide, a derivative of thalidomide, is an effective drug for myelodysplastic syndrome; lenalidomide binds the CRL4CRBN E3 ubiquitin ligase and promotes degradation of casein kinase 1a, on which the malignant cells rely for survival.

    • Jan Krönke
    • , Emma C. Fink
    •  & Benjamin L. Ebert

  • Article |

    Whereas previous structural investigation of ribosome inhibitors has been done using the prokaryotic ribosome, this work presents X-ray crystal structures of the yeast ribosome in complex with 16 inhibitors including eukaryotic-specific inhibitors; the inhibitors all bind the mRNA or tRNA binding sites, larger molecules appear to target specifically the first elongation cycle.

    • Nicolas Garreau de Loubresse
    • , Irina Prokhorova
    •  & Marat Yusupov

  • Letter |

    The crystal structure of prolyl tRNA synthetase simultaneously bound to its substrate ATP and its inhibitor halofuginone, a derivative of a compound used to treat malaria, indicates that (through interactions with ATP) halofuginone occupies both the amino acid and tRNA binding sites on the synthetase, revealing a new model for developing synthetase inhibitors.

    • Huihao Zhou
    • , Litao Sun
    •  & Paul Schimmel

  • News & Views |

    The synthesis of conolidine, a scarce, naturally occurring compound, has enabled the first studies of its pharmacological properties to be carried out. Excitingly, conolidine is a painkiller that seems to have an unusual mechanism of action.

    • Sarah E. Reisman

  • News & Views |

    Heart failure is characterized by weakened contractions of heart muscle. A drug that directly activates the key force-generating molecule in this muscle may be a valuable tool to strengthen the failing heart.

    • Donald M. Bers
    •  & Samantha P. Harris

  • Letter |

    The four receptors of the Notch family are transmembrane proteins through which mammalian cells communicate to regulate cell fate and growth. Aberrant signalling through each receptor has been linked to disease, so the Notch pathway is a compelling drug target. But current drugs cannot distinguish between the different Notch proteins. Here, phage display technology has been used to generate highly specialized antibodies, enabling the functions of Notch1 and Notch2 to be discriminated in humans and mice.

    • Yan Wu
    • , Carol Cain-Hom
    •  & Christian W. Siebel

  • Article |

    African sleeping sickness, caused by Trypanosoma brucei species, is responsible for some 30,000 human deaths each year. Available treatments are limited by poor efficacy and safety profiles. However, a new molecular target for potential treatments has now been identified. The protein target is T. brucei N-myristoyltransferase. In further experiments, lead compounds have been discovered that inhibit this protein, kill trypanosomes in vitro and in vivo, and can cure trypanosomiasis in mice.

    • Julie A. Frearson
    • , Stephen Brand
    •  & Paul G. Wyatt

  • News Feature |

    Questions about a laboratory assay are making Sirtris, a high-profile biotechnology company, the talking point of the ageing field. Heidi Ledford investigates.

    • Heidi Ledford

  • Letter |

    The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors.

    • Poulikos I. Poulikakos
    • , Chao Zhang
    •  & Neal Rosen

  • Letter |

    Worldwide, 170 million people are infected with the hepatitis C virus, which is a significant cause of liver-related illnesses and deaths. Standard treatment combines pegylated interferon alpha and ribavirin (RBV), but has some negative effects, notably RBV-induced haemolytic anaemia. Here, a genome-wide study shows that a deficiency in the enzyme inosine triphosphatase protects against haemolytic anaemia in patients receiving RBV.

    • Jacques Fellay
    • , Alexander J. Thompson
    •  & David B. Goldstein

  • Letter |

    The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors.

    • Georgia Hatzivassiliou
    • , Kyung Song
    •  & Shiva Malek

  • Article |

    The integrase protein of retroviruses such as HIV-1 catalyses insertion of the viral genome into that of the host. Here, the long-awaited structure of the full-length integrase complex is predicted, revealing not only details of the biochemistry of the integration reaction, but also the means by which current inhibitors affect this process.

    • Stephen Hare
    • , Saumya Shree Gupta
    •  & Peter Cherepanov

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