Browse Articles

  • Article |

    Structural and biochemical analyses identify Nudt12 as a novel mRNA deNADing enzyme in mammalian cells, which has a different substrate preference compared to the deNADing enzyme DXO.

    • Ewa Grudzien-Nogalska
    • , Yixuan Wu
    • , Xinfu Jiao
    • , Huijuan Cui
    • , Maria K. Mateyak
    • , Ronald P. Hart
    • , Liang Tong
    •  & Megerditch Kiledjian
  • Article |

    Structural analysis of uracil DNA glycosylases in complex with DNA reveals that conserved H109 acts as a nucleophile to attack the oxocarbenium ion and makes a covalent bond to the abasic site after uracil excision to form a stable intermediate.

    • Woo-Chan Ahn
    • , Shashanka Aroli
    • , Jin-Hahn Kim
    • , Jeong Hee Moon
    • , Ga Seal Lee
    • , Min-Ho Lee
    • , Pau Biak Sang
    • , Byung-Ha Oh
    • , Umesh Varshney
    •  & Eui-Jeon Woo
  • Article |

    Bioactive sesquiterpenes accumulating in petunia stigmas are synthesized in the floral tube and then transported to the pistil via natural fumigation within the internal airspace of the developing flower.

    • Benoît Boachon
    • , Joseph H. Lynch
    • , Shaunak Ray
    • , Jing Yuan
    • , Kristian Mark P. Caldo
    • , Robert R. Junker
    • , Sharon A. Kessler
    • , John A. Morgan
    •  & Natalia Dudareva
  • Article |

    A potent inhibitor for hepatocyte growth factor was identified that utilizes an allosteric mode of inhibition revealed by atomic force microscopy imaging. The inhibitor could be used for positron emission tomography imaging of mouse tumors.

    • Katsuya Sakai
    • , Toby Passioura
    • , Hiroki Sato
    • , Kenichiro Ito
    • , Hiroki Furuhashi
    • , Masataka Umitsu
    • , Junichi Takagi
    • , Yukinari Kato
    • , Hidefumi Mukai
    • , Shota Warashina
    • , Maki Zouda
    • , Yasuyoshi Watanabe
    • , Seiji Yano
    • , Mikihiro Shibata
    • , Hiroaki Suga
    •  & Kunio Matsumoto
  • Article |

    High-throughput screening identifies compounds that target insulin-degrading enzyme (IDE) and X-ray co-crystallography reveals how these compounds block insulin degradation by IDE but support its proteolysis of other substrates, including glucagon.

    • Juan Pablo Maianti
    • , Grace A. Tan
    • , Amedeo Vetere
    • , Amie J. Welsh
    • , Bridget K. Wagner
    • , Markus A. Seeliger
    •  & David R. Liu
  • Brief Communication |

    MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, interacts directly with NLRP3 at the Walker B motif that hydrolyzes ATP, as defined by a protease-susceptibility assay, mutational analysis, and surface plasmon resonance analysis.

    • Rebecca C. Coll
    • , James R. Hill
    • , Christopher J. Day
    • , Alina Zamoshnikova
    • , Dave Boucher
    • , Nicholas L. Massey
    • , Jessica L. Chitty
    • , James A. Fraser
    • , Michael P. Jennings
    • , Avril A. B. Robertson
    •  & Kate Schroder
  • Article |

    Optogenetically controlling the assembly of enzyme clusters enhances product formation and specificity during deoxyviolacein biosynthesis by decreasing concentrations of intermediate metabolites and reducing flux through competing pathways.

    • Evan M. Zhao
    • , Nathan Suek
    • , Maxwell Z. Wilson
    • , Elliot Dine
    • , Nicole L. Pannucci
    • , Zemer Gitai
    • , José L. Avalos
    •  & Jared E. Toettcher
  • Brief Communication |

    MCC950, a small-molecule inhibitor of the NLRP3 inflammasome, inactivates NLRP3, including hyperactive disease-linked mutations, by closing the ‘open’ conformation, thereby preventing conformational changes required for NLRP3 activation.

    • Ana Tapia-Abellán
    • , Diego Angosto-Bazarra
    • , Helios Martínez-Banaclocha
    • , Carlos de Torre-Minguela
    • , Jose P. Cerón-Carrasco
    • , Horacio Pérez-Sánchez
    • , Juan I. Arostegui
    •  & Pablo Pelegrin
  • News & Views |

    The NLRP3 inflammasome contributes to pathogenic inflammation in a broad range of diseases, making it a highly relevant drug target. Two studies published in this issue found an inhibitor of NLRP3 inflammasome activation to directly bind NLRP3 within its central NACHT domain, interfering with ATP hydrolysis and structural changes critical for NLRP3 oligomerization and subsequent inflammasome formation.

    • Oliver Gorka
    • , Emilia Neuwirt
    •  & Olaf Groß
  • Article |

    Sulfation of chondroitin sulfate and heparan sulfate dictates their abilities to promote axon growth via regulating the binding to the phosphatase PTPRσ and the consequences on phosphorylation of the cortactin component of the autophagy machinery.

    • Kazuma Sakamoto
    • , Tomoya Ozaki
    • , Yen-Chun Ko
    • , Cheng-Fang Tsai
    • , Yuanhao Gong
    • , Masayoshi Morozumi
    • , Yoshimoto Ishikawa
    • , Kenji Uchimura
    • , Satomi Nadanaka
    • , Hiroshi Kitagawa
    • , Medel Manuel L. Zulueta
    • , Anandaraju Bandaru
    • , Jun-ichi Tamura
    • , Shang-Cheng Hung
    •  & Kenji Kadomatsu
  • Article |

    A photoswitchable analog of spingosine-1-phosphate (S1P) that allows for modulation of the action of this bioactive lipid exhibits prolonged metabolic stability compared to S1P, activates S1P receptors in cells and mediates nociception in mice.

    • Johannes Morstein
    • , Rose Z. Hill
    • , Alexander J. E. Novak
    • , Suihan Feng
    • , Derek D. Norman
    • , Prashant C. Donthamsetti
    • , James A. Frank
    • , Takeshi Harayama
    • , Benjamin M. Williams
    • , Abby L. Parrill
    • , Gabor J. Tigyi
    • , Howard Riezman
    • , Ehud Y. Isacoff
    • , Diana M. Bautista
    •  & Dirk Trauner
  • Article |

    Reconstitution of β-Kdo-based capsular polysaccharide biosynthesis and crystallographic analysis of KpsC, a glycosyltransferase with two active sites for β-Kdo-glycolipid primer extension, reveal a new glycosyltransferase structural family.

    • Liam Doyle
    • , Olga G. Ovchinnikova
    • , Katharine Myler
    • , Evan Mallette
    • , Bo-Shun Huang
    • , Todd L. Lowary
    • , Matthew S. Kimber
    •  & Chris Whitfield
  • Article |

    Affinity-based target isolation and X-ray crystallography enabled identification of the non-protonophore ES9-17 as an inhibitor of the clathrin heavy chain in plants, enabling disruption of endocytosis.

    • Wim Dejonghe
    • , Isha Sharma
    • , Bram Denoo
    • , Steven De Munck
    • , Qing Lu
    • , Kiril Mishev
    • , Haydar Bulut
    • , Evelien Mylle
    • , Riet De Rycke
    • , Mina Vasileva
    • , Daniel V. Savatin
    • , Wim Nerinckx
    • , An Staes
    • , Andrzej Drozdzecki
    • , Dominique Audenaert
    • , Klaas Yperman
    • , Annemieke Madder
    • , Jiří Friml
    • , Daniël Van Damme
    • , Kris Gevaert
    • , Volker Haucke
    • , Savvas N. Savvides
    • , Johan Winne
    •  & Eugenia Russinova
  • News & Views |

    Endocytosis mediates the internalization of proteins and lipids at the plasma membrane and plays essential roles in plant growth and development. A new small molecule enables manipulation of plant endocytosis in an acute and transient manner.

    • Chunhua Zhang
    •  & Glenn R. Hicks
  • News & Views |

    Chemical probes that irreversibly inhibit protein function may be used across species to discover proteins. Combining phenotypic screening and activity-based protein profiling, a new study uncovers a discrete lipid signaling pathway regulating lifespan in the worm Caenorhabditis elegans.

    • Jürg Gertsch
  • Article |

    Single-molecule analysis by high-speed atomic force microscopy reveals that oxidized protein disulfide isomerase adopts a dynamic conformation in the absence of substrates and forms face-to-face dimers to accelerate oxidative folding in the presence of substrates.

    • Masaki Okumura
    • , Kentaro Noi
    • , Shingo Kanemura
    • , Misaki Kinoshita
    • , Tomohide Saio
    • , Yuichi Inoue
    • , Takaaki Hikima
    • , Shuji Akiyama
    • , Teru Ogura
    •  & Kenji Inaba
  • Article |

    A CRISPR–Cas9 screening-based structure–activity relationship profiling method reveals that LSD1 inhibitors suppress acute myeloid leukemia by disruption of the interaction between LSD1 and GFI1B instead of the enzyme activity of LSD1.

    • Michael E. Vinyard
    • , Cindy Su
    • , Allison P. Siegenfeld
    • , Amanda L. Waterbury
    • , Allyson M. Freedy
    • , Pallavi M. Gosavi
    • , Yongho Park
    • , Eugene E. Kwan
    • , Benjamin D. Senzer
    • , John G. Doench
    • , Daniel E. Bauer
    • , Luca Pinello
    •  & Brian B. Liau
  • Article |

    A chemogenomic approach to explore activity of the free fatty acid receptor FFA2 independently of the related FFA3 shows that FFA2 in differentiated adipocytes and colonic crypt cells in mice is responsible for regulated lipolysis and GLP-1 release.

    • Daniele Bolognini
    • , Natasja Barki
    • , Adrian J. Butcher
    • , Brian D. Hudson
    • , Eugenia Sergeev
    • , Colin Molloy
    • , Catherine E. Moss
    • , Sophie J. Bradley
    • , Christian Le Gouill
    • , Michel Bouvier
    • , Andrew B. Tobin
    •  & Graeme Milligan
  • Article |

    Structural analysis of Mango-III in complex with fluorophores reveals a globular architecture and a planar conformation of fluorophores. Structure-guided mutation and functional reselection identified two mutants with improved fluorescence intensity.

    • Robert J. Trachman III
    • , Alexis Autour
    • , Sunny C. Y. Jeng
    • , Amir Abdolahzadeh
    • , Alessio Andreoni
    • , Razvan Cojocaru
    • , Ramil Garipov
    • , Elena V. Dolgosheina
    • , Jay R. Knutson
    • , Michael Ryckelynck
    • , Peter J. Unrau
    •  & Adrian R. Ferré-D’Amaré
  • Article |

    A chromatin-focused chemical screen identified CBP/EP300 bromodomain inhibitors as enhancers of reprogramming. These inhibitors decrease histone H3 lysine 27 acetylation, chromatin accessibility and expression of somatic-specific genes.

    • Ayyub Ebrahimi
    • , Kenan Sevinç
    • , Gülben Gürhan Sevinç
    • , Adam P. Cribbs
    • , Martin Philpott
    • , Fırat Uyulur
    • , Tunç Morova
    • , James E. Dunford
    • , Sencer Göklemez
    • , Şule Arı
    • , Udo Oppermann
    •  & Tamer T. Önder
  • Article |

    Structural and biochemical characterization of arginine kinase McsB reveals how its phosphagen kinase–like catalytic domain is adapted to target protein substrates while its phosphoarginine-binding domain allosterically controls kinase activity.

    • Marcin J. Suskiewicz
    • , Bence Hajdusits
    • , Rebecca Beveridge
    • , Alexander Heuck
    • , Lam Dai Vu
    • , Robert Kurzbauer
    • , Katja Hauer
    • , Vanessa Thoeny
    • , Klaus Rumpel
    • , Karl Mechtler
    • , Anton Meinhart
    •  & Tim Clausen
  • News & Views |

    Arginine protein kinases regulate bacterial signaling cascades through phosphorylation of key arginine residues. Crystal structures of the kinase McsB provide the first glimpse of how these unusual enzymes recognize their protein substrates and are allosterically regulated.

    • Titus J. Boggon
  • Article |

    Combinatorial shuffling of peptide sequence modules, post-translational modification and screening with a high-throughput growth inhibition assay results in the identification of lanthipeptide variants with altered antibacterial activities.

    • Steven Schmitt
    • , Manuel Montalbán-López
    • , David Peterhoff
    • , Jingjing Deng
    • , Ralf Wagner
    • , Martin Held
    • , Oscar P. Kuipers
    •  & Sven Panke
  • Article |

    Genetic, structural and biochemical analysis identifies GacH as a glycerol phosphate transferase that modifies N-acetylglucosamine components of group A carbohydrates (GAC) in streptococcal cell walls.

    • Rebecca J. Edgar
    • , Vincent P. van Hensbergen
    • , Alessandro Ruda
    • , Andrew G. Turner
    • , Pan Deng
    • , Yoann Le Breton
    • , Najib M. El-Sayed
    • , Ashton T. Belew
    • , Kevin S. McIver
    • , Alastair G. McEwan
    • , Andrew J. Morris
    • , Gérard Lambeau
    • , Mark J. Walker
    • , Jeffrey S. Rush
    • , Konstantin V. Korotkov
    • , Göran Widmalm
    • , Nina M. van Sorge
    •  & Natalia Korotkova
  • Brief Communication |

    Orange CaMBI, a genetically encoded bioluminescent calcium indicator consisting of calcium-sensing domain CaM, luciferase, and fluorescent proteins, reports calcium dynamics in single cells and reveals calcium oscillations in whole mouse organs.

    • Younghee Oh
    • , Yunhee Park
    • , Julia H. Cho
    • , Haodi Wu
    • , Nicole K. Paulk
    • , Lan Xiang Liu
    • , Namdoo Kim
    • , Mark A. Kay
    • , Joseph C. Wu
    •  & Michael Z. Lin
  • News & Views |

    The molybdenum cofactor (Moco) is a fragile prosthetic group essential for most organisms. Nematodes are now capable of extracting Moco from their bacterial diet to mediate detoxification of sulfite.

    • Ralf R. Mendel
    •  & Thomas W. Hercher
  • Article |

    Phenotypic screening identifies a small-molecule inhibitor of the C. elegans serine hydrolase FAAH-4 that promotes longevity and identifies the enzyme as the functional homolog of mammalian monoacylglycerol lipase (MAGL).

    • Alice L. Chen
    • , Kenneth M. Lum
    • , Pablo Lara-Gonzalez
    • , Daisuke Ogasawara
    • , Armand B Cognetta III
    • , Alan To
    • , William H. Parsons
    • , Gabriel M. Simon
    • , Arshad Desai
    • , Michael Petrascheck
    • , Liron Bar-Peled
    •  & Benjamin F. Cravatt
  • Article |

    An engineered biosensor, which optimizes metal-sensing and couples it to transcriptional amplification cascades that produce a fluorescent protein, was applied to build a sensitive and easy-to-use sensor for the toxic metals As3+ and Hg2+.

    • Xinyi Wan
    • , Francesca Volpetti
    • , Ekaterina Petrova
    • , Chris French
    • , Sebastian J. Maerkl
    •  & Baojun Wang
  • News & Views |

    The N6-methyladenosine modification next to the 5′ RNA cap has dynamic regulatory functions. Recent findings show that this modification regulates the splicing and translational activity of different classes of RNAs.

    • Richard A. Padgett
  • Article |

    Enzymes from two discrete biosynthetic gene clusters in the entomopathogenic bacterium Xenorhabdus szentirmaii cooperate to produce a diverse array of phenazine natural products, including phenazine–peptide and phenazine–polyketide derivatives.

    • Yi-Ming Shi
    • , Alexander O. Brachmann
    • , Margaretha A. Westphalen
    • , Nick Neubacher
    • , Nicholas J. Tobias
    •  & Helge B. Bode
  • News & Views |

    Powerful combinatorial peptide library methods allow the discovery of peptide leads from diverse libraries. A new platform based on tandem mass spectrometry peptide sequencing coupled with high-performance size-exclusion chromatography enables identification of high-affinity peptidic ligands from focused libraries.

    • Kit S. Lam
  • Article |

    Neopinone isomerase catalyzes the isomerization of the opiate alkaloid neopinone to codeinone, driving the biosynthesis of codeine and morphine and preventing accumulation of their isomers neopine and neomorphine.

    • Mehran Dastmalchi
    • , Xue Chen
    • , Jillian M. Hagel
    • , Limei Chang
    • , Rongji Chen
    • , Sukanya Ramasamy
    • , Sam Yeaman
    •  & Peter J. Facchini
  • Article |

    Affinity-based selection in solution enables the identification of high-affinity ligands for disrupting the MDM2–p53 interaction and binding to the HIV capsid protein from libraries of both linear and cyclic peptides containing non-canonical amino acids.

    • Fayçal Touti
    • , Zachary P. Gates
    • , Anupam Bandyopadhyay
    • , Guillaume Lautrette
    •  & Bradley L. Pentelute