Structure-based drug design articles within Nature

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  • Article |

    Modular synthesis and structural biology are used to design and characterize group A streptogramin antibiotics, one of which has activity against streptogramin-resistant strains and demonstrates efficacy in a mouse model of bacterial infection.

    • Qi Li
    • , Jenna Pellegrino
    •  & Ian B. Seiple

  • Article |

    The MYST acetyltransferase HBO1 is a critical regulator in maintaining leukaemia stem cells, and a small-molecule inhibitor of HBO1 is developed that shows efficacy against a range of acute myeloid leukaemia cells.

    • Laura MacPherson
    • , Juliana Anokye
    •  & Mark A. Dawson

  • Article |

    High-resolution crystal structures of the rat succinate receptor SUCNR1 in an inactive confirmation, and the humanized rat SUCNR1 bound to an antagonist, provide insights into the structure of these receptors and the species selectivity of antagonist binding.

    • Matthias Haffke
    • , Dominique Fehlmann
    •  & Veli-Pekka Jaakola

  • Letter |

    Crystal structures of the human cannabinoid receptor 1 (CB1) bound to the agonists AM11542 and AM841 reveal notable structural rearrangements upon receptor activation, and this flexibility may be a common feature among other G-protein-coupled receptors.

    • Tian Hua
    • , Kiran Vemuri
    •  & Zhi-Jie Liu

  • Article |

    Crystal structures of two complexes of the angiotensin II receptor AT2R with distinct tightly bound ligands reveal an active-like state of the receptor, in which helix VIII adopts a non-canonical position that blocks binding of G proteins and β-arrestins.

    • Haitao Zhang
    • , Gye Won Han
    •  & Vadim Cherezov

  • Article |

    The X-ray crystal structure of the human G-protein-coupled receptor protease-activated receptor 1 (PAR1) bound to the antagonist vorapaxar is solved, revealing an unusual method of drug binding that should facilitate the development of improved PAR1-selective antagonists.

    • Cheng Zhang
    • , Yoga Srinivasan
    •  & Brian K. Kobilka

  • News & Views |

    Developing therapeutic drugs that target peptide receptors is challenging. The structure of one of these G-protein-coupled receptors, NTS1, activated and bound to a peptide, provides an excellent starting point. See Article p.508

    • Felix Hausch
    •  & Florian Holsboer

  • Letter |

    The mechanism of action of general anaesthetics is poorly understood, although there is some evidence that their principal protein targets are pentameric ligand-gated ion channels (pLGICs). Here, the X-ray crystal structures of propofol and desflurane bound to a bacterial homologue of the pLGIC family are solved. The structures reveal a common binding site for these two anaesthetics in the upper part of the transmembrane domain of each protomer.

    • Hugues Nury
    • , Catherine Van Renterghem
    •  & Pierre-Jean Corringer

  • Letter |

    Here, the X-ray crystal structure of the β1 adrenergic receptor, a G-protein-coupled receptor, bound to four small molecules that either act as full agonists or partial agonists is solved. The structures show that agonist binding induces a contraction of the catecholamine-binding pocket relative to the antagonist-bound receptor. This work reveals the pharmacological differences between different ligand classes, which should facilitate the structure-based design of new drugs with predictable efficacies.

    • Tony Warne
    • , Rouslan Moukhametzianov
    •  & Christopher G. Tate

  • Article |

    The X-ray crystal structure of the human β2 adrenergic receptor, a G-protein-coupled receptor, in an agonist-bound 'active' state is solved. Comparison of this structure with a previously published structure of the same GPCR in an inactive state indicates that minor changes in the binding pocket of the protein lead to major changes elsewhere — there is a large outward movement of the cytoplasmic end of one of the transmembrane segments and rearrangements of two other transmembrane segments. This structure provides insights into the process of agonist binding and activation.

    • Søren G. F. Rasmussen
    • , Hee-Jung Choi
    •  & Brian K. Kobilka

  • Article |

    Enzymes that move along DNA, such as DNA and RNA polymerases, cause the DNA ahead of them to become supercoiled. This would lead to the DNA becoming overwound, were the stress not relieved by topoisomerases. Topoisomerase inhibitors have been used as antibacterial and anticancer drugs, but the structural basis for their activity has been unclear. Here, the crystal structures are presented of a topoisomerase on DNA, either alone or in the presence of a new type of antibiotic.

    • Benjamin D. Bax
    • , Pan F. Chan
    •  & Michael N. Gwynn

  • News & Views |

    It is hard to predict how strongly a small molecule will bind to a protein, but this is a crucial goal of computer-aided drug discovery. A new approach models the forcible removal of molecules from a protein's active site.

    • William L. Jorgensen

  • Letter |

    G-protein-coupled receptors (GPCRs) mediate the majority of cellular responses to hormones and neurotransmitters and are the largest group of therapeutic targets for a range of diseases. The extracellular surface (ECS) of GPCRs is diverse and therefore an ideal target for the discovery of subtype-selective drugs. Here, NMR spectroscopy is used to investigate ligand-specific conformational changes around a central structural feature in the ECS of a GPCR.

    • Michael P. Bokoch
    • , Yaozhong Zou
    •  & Brian K. Kobilka

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