Chemical biology

  • Article |

    Bacteria in the human gut and oral microbiome encode enzymes that selectively phosphorylate the antidiabetic drug acarbose—an inhibitor of both human and bacterial α-glucosidases—resulting in its inactivation and limiting the drug's effects on the ability of the host to metabolize complex carbohydrates.

    • Jared Balaich
    • , Michael Estrella
    •  & Mohamed S. Donia
  • Article |

    Structural studies of the itch receptors MRGPRX2 and MRGPRX4 in complex with endogenous and synthetic ligands provide a basis for the development of therapeutic compounds for pain, itch and mast cell-mediated hypersensitivity.

    • Can Cao
    • , Hye Jin Kang
    •  & Bryan L. Roth
  • Article |

    Cyclopamine and its chemical analogue A3E inhibit replication of human respiratory syncytial virus (RSV) by hardening the liquid–liquid phase-separated inclusion bodies, resulting in the inhibition of virus replication in the lungs of RSV-infected mice.

    • Jennifer Risso-Ballester
    • , Marie Galloux
    •  & Ralf Altmeyer
  • Article
    | Open Access

    Cryo-electron microscopy structure of heterodimeric GABAB receptor in complex with Gi1 protein reveals that the mode of G-protein binding in this class-C G-protein-coupled receptor differs from that of other classes.

    • Cangsong Shen
    • , Chunyou Mao
    •  & Jianfeng Liu
  • Article |

    A modular de novo designed biosensor platform consisting of a cage and key molecule is developed, and used to create sensors for seven distinct proteins including the spike protein from SARS-CoV-2 and anti-SARS antibodies.

    • Alfredo Quijano-Rubio
    • , Hsien-Wei Yeh
    •  & David Baker
  • Article |

    Psychedelic alkaloids served as lead structures for the development of tabernanthalog, a non-hallucinogenic and non-toxic analogue that reduces alcohol- and heroin-seeking behaviour and produces antidepressant-like effects in rodents.

    • Lindsay P. Cameron
    • , Robert J. Tombari
    •  & David E. Olson
  • 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
  • Article |

    A methyltransferase ribozyme, along with the small-molecule cofactor O6-methylguanine, is shown to catalyse the site-specific installation of 1-methyladenosine in various RNAs, providing insights into the catalytic abilities of RNA.

    • Carolin P. M. Scheitl
    • , Mohammad Ghaem Maghami
    •  & Claudia Höbartner
  • Article |

    Analysis of two homologous groups of fungal pericyclases demonstrates how they can catalyse either an Alder-ene reaction—which has not previously been found in nature—or a hetero-Diels–Alder reaction.

    • Masao Ohashi
    • , Cooper S. Jamieson
    •  & Yi Tang
  • Article |

    The cellular organelles peroxisomes contribute to the sensitivity of cells to ferroptosis by synthesizing polyunsaturated ether phospholipids, and changes in the abundances of these lipids are associated with altered sensitivity to ferroptosis during cell-state transitions.

    • Yilong Zou
    • , Whitney S. Henry
    •  & Stuart L. Schreiber
  • Article |

    Crystal structures of the MEK kinase bound to the scaffold protein KSR and various MEK inhibitors, including the anti-cancer drug trametinib, reveal the molecular and functional mechanisms behind MEK inhibition.

    • Zaigham M. Khan
    • , Alexander M. Real
    •  & Arvin C. Dar
  • Article |

    4-Vinylanisole, which is emitted by gregarious locusts or as a result of aggregation of solitary locusts, is identified as an aggregation pheromone that strongly attracts both solitary and gregarious locusts, acting via the olfactory receptor OR35.

    • Xiaojiao Guo
    • , Qiaoqiao Yu
    •  & Le Kang
  • Article |

    Lysosome-targeting chimaeras—in which a small molecule or antibody is connected to a glycopeptide ligand to form a conjugate that can bind a cell-surface lysosome-shuttling receptor and a protein target—are used to achieve the targeted degradation of extracellular and membrane proteins.

    • Steven M. Banik
    • , Kayvon Pedram
    •  & Carolyn R. Bertozzi
  • Article |

    Cryo-electron microscopy structures of heterodimeric and homodimeric full-length GABAB receptors, combined with cellular signalling assays, shed light on the mechanisms that underpin signal transduction mediated by these receptors.

    • Makaía M. Papasergi-Scott
    • , Michael J. Robertson
    •  & Georgios Skiniotis
  • Article |

    A computational screen of an ultra-large virtual library against the structure of the melatonin receptor found nanomolar ligands, and ultimately two selective MT1 inverse agonists that induced phase advancement of the mouse circadian clock when given at subjective dusk.

    • Reed M. Stein
    • , Hye Jin Kang
    •  & Margarita L. Dubocovich
  • Article |

    Compounds that interact with mutant huntingtin and an autophagosomal protein are able to reduce cellular levels of mutant huntingtin by targeting it for autophagic degradation, demonstrating an approach that may have potential for treating proteopathies.

    • Zhaoyang Li
    • , Cen Wang
    •  & Boxun Lu
  • Article |

    The cryo-EM structure of the zebrafish cation–chloride cotransporter NKCC1 reveals the domain organization, ion translocation pathway, ion-binding sites and key residues for binding activity, providing insights into the activity of this family of transporter proteins with key roles in physiology.

    • Thomas A. Chew
    • , Benjamin J. Orlando
    •  & Liang Feng
  • Letter |

    A hydrolytic enzyme with a non-canonical organocatalytic mechanism was generated by introducing Nδ-methylhistidine into a designed active site using engineered translation components, allowing optimization of enzyme performance using laboratory evolution.

    • Ashleigh J. Burke
    • , Sarah L. Lovelock
    •  & Anthony P. Green
  • Letter |

    Microbial generation of a terminal-alkyne-containing amino acid can be encoded into E. coli and provides the potential for in vivo generation of proteins and natural products for click chemistry.

    • J. A. Marchand
    • , M. E. Neugebauer
    •  & M. C. Y. Chang
  • Article |

    Using a make-on-demand library that contains hundreds-of-millions of molecules, structure-based docking was used to identify compounds that, after synthesis and testing, are shown to interact with AmpC β-lactamase and the D4 dopamine receptor with high affinity.

    • Jiankun Lyu
    • , Sheng Wang
    •  & John J. Irwin
  • Article |

    Cryo-electron microscopy structures are reported in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA, and the benzodiazepines alprazolam and diazepam.

    • Simonas Masiulis
    • , Rooma Desai
    •  & A. Radu Aricescu