Latest Research

  • Article |

    Synthetic gene circuits regulated by small molecules have been used to fine-tune glycosyltransferase expression in CHO cells, providing a method to produce therapeutic monoclonal antibodies with precise glycosylation states.

    • Michelle M. Chang
    • , Leonid Gaidukov
    • , Giyoung Jung
    • , Wen Allen Tseng
    • , John J. Scarcelli
    • , Richard Cornell
    • , Jeffrey K. Marshall
    • , Jonathan L. Lyles
    • , Paul Sakorafas
    • , An-Hsiang Adam Chu
    • , Kaffa Cote
    • , Boriana Tzvetkova
    • , Sepideh Dolatshahi
    • , Madhuresh Sumit
    • , Bhanu Chandra Mulukutla
    • , Douglas A. Lauffenburger
    • , Bruno Figueroa Jr.
    • , Nevin M. Summers
    • , Timothy K. Lu
    •  & Ron Weiss
  • Article |

    Rewiring of bacterial two-component systems (TCSs) was achieved by DNA-binding domain swapping of the two largest response regulator families, which enables cross-species porting and provides a tool for identifying ligands for uncharacterized TCSs.

    • Sebastian R. Schmidl
    • , Felix Ekness
    • , Katri Sofjan
    • , Kristina N.-M. Daeffler
    • , Kathryn R. Brink
    • , Brian P. Landry
    • , Karl P. Gerhardt
    • , Nikola Dyulgyarov
    • , Ravi U. Sheth
    •  & Jeffrey J. Tabor
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • Article |

    A genetically encoded array to amplify signals for live-cell single-molecule fluorescence imaging allows unlimited temporal resolution through exchange of fluorophores and can be used to monitor the dynamics of histones, kinesins and integrins.

    • Rajarshi P. Ghosh
    • , J. Matthew Franklin
    • , Will E. Draper
    • , Quanming Shi
    • , Bruno Beltran
    • , Andrew J. Spakowitz
    •  & Jan T. Liphardt
  • Addendum |

    • Jacob I Stuckey
    • , Bradley M Dickson
    • , Nancy Cheng
    • , Yanli Liu
    • , Jacqueline L Norris
    • , Stephanie H Cholensky
    • , Wolfram Tempel
    • , Su Qin
    • , Katherine G Huber
    • , Cari Sagum
    • , Karynne Black
    • , Fengling Li
    • , Xi-Ping Huang
    • , Bryan L Roth
    • , Brandi M Baughman
    • , Guillermo Senisterra
    • , Samantha G Pattenden
    • , Masoud Vedadi
    • , Peter J Brown
    • , Mark TBedford
    • , Jinrong Min
    • , Cheryl H Arrowsmith
    • , Lindsey I James
    •  & Stephen V Frye
  • Article |

    Single-molecule FRET shows that a loop, which forms the selectivity filter in the bacterial inwardly rectifying K+ channel KirBac1.1, transitions between constrained and dilated conformations depending on ion occupancy of the filter.

    • Shizhen Wang
    • , Sun-Joo Lee
    • , Grigory Maksaev
    • , Xin Fang
    • , Chong Zuo
    •  & Colin G. Nichols
  • Article |

    Structural analysis of HIF-2α in complex with agonists and antagonists reveal that chemical ligands regulate the activity of HIF-2α by affecting the stability of the HIF-2α–ARNT heterodimer via redirecting residues in the PAS-B pocket.

    • Dalei Wu
    • , Xiaoyu Su
    • , Jingping Lu
    • , Sheng Li
    • , Becky L. Hood
    • , Stefan Vasile
    • , Nalini Potluri
    • , Xiaotong Diao
    • , Youngchang Kim
    • , Sepideh Khorasanizadeh
    •  & Fraydoon Rastinejad
  • Article |

    Two different methylation states of the adenosine adjacent to the snRNA cap are found in the biogenesis process of snRNAs, Am and m6Am, whose levels are regulated by FTO and are related to alternative pre-mRNA splicing.

    • Jan Mauer
    • , Miriam Sindelar
    • , Vladimir Despic
    • , Théo Guez
    • , Ben R. Hawley
    • , Jean-Jacques Vasseur
    • , Andrea Rentmeister
    • , Steven S. Gross
    • , Livio Pellizzoni
    • , Françoise Debart
    • , Hani Goodarzi
    •  & Samie R. Jaffrey
  • Article |

    A method combining genetic-code expansion, bioorthogonal Staudinger reduction and sortase-mediated transpeptidation enables site-specific and orthogonal modification of proteins with ubiquitin and SUMO in vitro and in living cells.

    • Maximilian Fottner
    • , Andreas-David Brunner
    • , Verena Bittl
    • , Daniel Horn-Ghetko
    • , Alexander Jussupow
    • , Ville R. I. Kaila
    • , Anja Bremm
    •  & Kathrin Lang
  • Article |

    A comprehensive analysis of the effect of the side chain composition of nucleic acid polymers revealed that the polarity of the side chains determines the performance of polymers during in vitro selections for protein binding.

    • Phillip A. Lichtor
    • , Zhen Chen
    • , Nadine H. Elowe
    • , Jonathan C. Chen
    •  & David R. Liu
  • Article |

    A small molecule that inhibits the interaction between BRAG2, a guanine-nucleotide exchange factor for the small GTPase Arf, and the membrane affects exchange factor function at the Golgi and suggests a role for BRAG2 in breast cancer.

    • Agata Nawrotek
    • , Sarah Benabdi
    • , Supaporn Niyomchon
    • , Marie-Hélène Kryszke
    • , Christophe Ginestier
    • , Tatiana Cañeque
    • , Livia Tepshi
    • , Angelica Mariani
    • , Robert P. St.Onge
    • , Guri Giaever
    • , Corey Nislow
    • , Emmanuelle Charafe-Jauffret
    • , Raphaël Rodriguez
    • , Mahel Zeghouf
    •  & Jacqueline Cherfils
  • Article |

    Using biochemical and NMR studies, a class of small-molecule inhibitors termed BAX activation inhibitors were found to bind directly to a previously unrecognized pocket of inactive BAX and allosterically inhibit conformational changes in BAX.

    • Thomas P. Garner
    • , Dulguun Amgalan
    • , Denis E. Reyna
    • , Sheng Li
    • , Richard N. Kitsis
    •  & Evripidis Gavathiotis
  • Article |

    Chemoproteomic mapping of fumarate sensitive cysteines in a hereditary leiomyomatosis and renal cell carcinoma cell line revealed a critical cysteine in the protein–protein interaction interface of the SWI–SNF complex.

    • Rhushikesh A. Kulkarni
    • , Daniel W. Bak
    • , Darmood Wei
    • , Sarah E. Bergholtz
    • , Chloe A. Briney
    • , Jonathan H. Shrimp
    • , Aktan Alpsoy
    • , Abigail L. Thorpe
    • , Arissa E. Bavari
    • , Daniel R. Crooks
    • , Michaella Levy
    • , Laurence Florens
    • , Michael P. Washburn
    • , Norma Frizzell
    • , Emily C. Dykhuizen
    • , Eranthie Weerapana
    • , W. Marston Linehan
    •  & Jordan L. Meier
  • Article |

    Combining X-ray structures, surface plasmon resonance and hydrogen-deuterium exchange–mass spectrometry, a class of highly selective inhibitors was found to bind to an active state of PI3Kγ breaking a conformational ‘lock’ important for activation of PI3Kγ.

    • Gangadhara Gangadhara
    • , Göran Dahl
    • , Thomas Bohnacker
    • , Rebecca Rae
    • , Jenny Gunnarsson
    • , Stefan Blaho
    • , Linda Öster
    • , Helena Lindmark
    • , Kostas Karabelas
    • , Nils Pemberton
    • , Christian Tyrchan
    • , Mickael Mogemark
    • , Matthias P. Wymann
    • , Roger L. Williams
    • , Matthew W. D. Perry
    • , Tineke Papavoine
    •  & Jens Petersen