Volume 14 Issue 12, December 2018

Volume 14 Issue 12

Th17 cells get inflamed

Several compounds, including the HIV protease inhibitor ritonavir and a synthetic peptide, disrupt the interaction between CD95 (blue ribbon) and PLCγ1 (orange ribbon) by mimicking the structure of the CD95/Fas calcium-inducing domain, which mediates binding to PLCγ1 at the membrane (grey sticks). These inhibitors limit calcium signaling and Th17 migration driven by the soluble CD95 ligand, s-CD95L, as well as inflammation in lupus mice. In HIV patients treated with HIV protease inhibitors, PBMCs show impairment of the non-apoptotic pro-migratory CD95 pathway.

See Legembre et al.

Image: Patrick Legembre. Cover design: Erin Dewalt

Research Highlights

News & Views

  • News & Views |

    Current drug discovery efforts focus on proteins because of their ability to form stable, structured pockets. A recent study demonstrates that targeting stable, structured bioactive RNA motifs, such as autocatalytic introns, may provide a novel method of expanding druggability and selectivity.

    • James Palacino
  • News & Views |

    Terpenoids are assembled from five-carbon (C5) units, which limits the available scaffold chemical space for the discovery of bioactive molecules. A combination of enzyme and metabolic engineering now enables biosynthesis of a plethora of non-natural C11 terpenoids.

    • Yongjin J. Zhou
  • News & Views |

    Scientists have combined functional and computational analysis to predict the substrate specificity of a family of glycosyltransferases from Arabidopsis thaliana, creating a tool that enables researchers to classify the donor and acceptor specificity of glycosyltransferase enzymes.

    • Jochen Schmid

Articles

  • Article |

    High-throughput screening followed by an examination of structure–activity relationship-based optimization resulted in the identification of potent small-molecule inhibitors of group IIB intron splicing in fungal organisms.

    • Olga Fedorova
    • , G. Erik Jagdmann Jr.
    • , Rebecca L. Adams
    • , Lin Yuan
    • , Michael C. Van Zandt
    •  & Anna Marie Pyle
  • Article |

    The HIV protease inhibitor ritonavir targets the calcium-inducing domain (CID) of CD95 to block interactions with PLCγ1. Peptidomimetics targeting the CD95 CID prevents accumulation of inflammatory Th17 cells observed in systemic lupus erythematosus.

    • Amanda Poissonnier
    • , Jean-Philippe Guégan
    • , Ha Thanh Nguyen
    • , Daniel Best
    • , Nicolas Levoin
    • , Guennadi Kozlov
    • , Kalle Gehring
    • , Raphael Pineau
    • , Florence Jouan
    • , Lucie Morere
    • , Sophie Martin
    • , Mélissa Thomas
    • , Estibaliz Lazaro
    • , Isabelle Douchet
    • , Thomas Ducret
    • , Pierre van de Weghe
    • , Patrick Blanco
    • , Mickael Jean
    • , Pierre Vacher
    •  & Patrick Legembre
  • Article |

    Yeast engineered to produce the six-carbon terpene building block 2-methyl-geranyl diphosphate, coupled with terpene synthases engineered to accept this noncanonical substrate, enables the biosynthesis of a collection of new C11 terpenoid scaffolds.

    • Codruta Ignea
    • , Marianna Pontini
    • , Mohammed S. Motawia
    • , Massimo E. Maffei
    • , Antonios M. Makris
    •  & Sotirios C. Kampranis
  • Article |

    High-throughput screening and activity-based protein profiling find a selective and in vivo–active inhibitor of the membrane-associated serine hydrolase ABHD12 that alters lysophospholipid content and has immunostimulatory effects.

    • Daisuke Ogasawara
    • , Taka-Aki Ichu
    • , Vincent F. Vartabedian
    • , Jacqueline Benthuysen
    • , Hui Jing
    • , Alex Reed
    • , Olesya A. Ulanovskaya
    • , Jonathan J. Hulce
    • , Amanda Roberts
    • , Steven Brown
    • , Hugh Rosen
    • , John R. Teijaro
    •  & Benjamin F. Cravatt
  • Article |

    Bioinformatic analysis coupled to substrate-reactivity profiling for the glycosyltransferase (GT) enzyme superfamily supports the development of ‘GT-Predict’ as a tool for functional prediction of GT–substrate relationships.

    • Min Yang
    • , Charlie Fehl
    • , Karen V. Lees
    • , Eng-Kiat Lim
    • , Wendy A. Offen
    • , Gideon J. Davies
    • , Dianna J. Bowles
    • , Matthew G. Davidson
    • , Stephen J. Roberts
    •  & Benjamin G. Davis
  • Article |

    The use of an allosteric drug-design method resulted in the identification of a first-in-class cellularly active SIRT6 activator that induces cell-cycle arrest in the G0–G1 phase, thus suppressing proliferation in human hepatocellular carcinoma cells.

    • Zhimin Huang
    • , Junxing Zhao
    • , Wei Deng
    • , Yingyi Chen
    • , Jialin Shang
    • , Kun Song
    • , Lu Zhang
    • , Chengxiang Wang
    • , Shaoyong Lu
    • , Xiuyan Yang
    • , Bin He
    • , Jinrong Min
    • , Hao Hu
    • , Minjia Tan
    • , Jianrong Xu
    • , Qiufen Zhang
    • , Jie Zhong
    • , Xiaoxiang Sun
    • , Zhiyong Mao
    • , Houwen Lin
    • , Mingzhe Xiao
    • , Y Eugene Chin
    • , Hualiang Jiang
    • , Ying Xu
    • , Guoqiang Chen
    •  & Jian Zhang
  • Article |

    Structural and biochemical analysis of propionyl-CoA synthase reveals that it forms a reaction chamber containing three active sites, which sequesters the reactive intermediate acrylyl-CoA during the conversion of 3-hydroxypropionate to propionyl-CoA.

    • Iria Bernhardsgrütter
    • , Bastian Vögeli
    • , Tristan Wagner
    • , Dominik M. Peter
    • , Niña Socorro Cortina
    • , Jörg Kahnt
    • , Gert Bange
    • , Sylvain Engilberge
    • , Eric Girard
    • , François Riobé
    • , Olivier Maury
    • , Seigo Shima
    • , Jan Zarzycki
    •  & Tobias J. Erb
  • Article |

    The freshwater microcrustacean Daphnia pulex forms defensive neckteeth in response to a collection of chemical cues (the kairomone), now identified as certain fatty acids conjugated to glutamine, released during digestion by its predator Chaoborus.

    • Linda C. Weiss
    • , Bauke Albada
    • , Sina M. Becker
    • , Sven W. Meckelmann
    • , Julia Klein
    • , Martin Meyer
    • , Oliver J. Schmitz
    • , Ulf Sommer
    • , Markus Leo
    • , Johannes Zagermann
    • , Nils Metzler-Nolte
    •  & Ralph Tollrian
  • Article |

    An inhibitor of the YEATS domain was developed by targeting a unique π-π-π stacking in the YEATS–Kcr recognition. An ENL YEATS-selective inhibitor, XL-13m, helps probe the YEATS-dependent role of ENL in the leukemogenic transcription program.

    • Xin Li
    • , Xiao-Meng Li
    • , Yixiang Jiang
    • , Zheng Liu
    • , Yiwen Cui
    • , Ka Yi Fung
    • , Stan H. E. van der Beelen
    • , Gaofei Tian
    • , Liling Wan
    • , Xiaobing Shi
    • , C. David Allis
    • , Haitao Li
    • , Yuanyuan Li
    •  & Xiang David Li
  • Article |

    A structural study supported by molecular dynamics simulations describes the basis of receptor-subtype selectivity of a small-molecule antagonist of the human muscarinic M2 receptor.

    • Ryoji Suno
    • , Sangbae Lee
    • , Shoji Maeda
    • , Satoshi Yasuda
    • , Keitaro Yamashita
    • , Kunio Hirata
    • , Shoichiro Horita
    • , Maki S. Tawaramoto
    • , Hirokazu Tsujimoto
    • , Takeshi Murata
    • , Masahiro Kinoshita
    • , Masaki Yamamoto
    • , Brian K. Kobilka
    • , Nagarajan Vaidehi
    • , So Iwata
    •  & Takuya Kobayashi