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  • Feature |

    We asked a collection of chemical biologists, “What was the most exciting research achievement or technology innovation in chemical biology in the last five years?” and reveal some of the perspectives we received.

  • Feature |

    We present a selection of papers published in Nature Chemical Biology over the past five years that reflect the diversity and excitement of chemical biology research.

  • Editorial |

    Over the past decade and a half, chemical biology has crystallized as a discipline and extended its reach into new scientific areas, but the field’s greatest promise lies ahead.

  • Perspective |

    This Perspective highlights emerging themes in the inter-regulation of the genome and metabolism via chromatin, including nonenzymatic histone modifications, cofactor-promiscuous chromatin-modifying enzymes, and subnucleocytoplasmic metabolite pools.

    • Katharine L. Diehl
    •  & Tom W. Muir

  • News & Views |

    The discovery of selective modulators of two Cryptochrome isoforms, CRY1 and CRY2, permits a deeper understanding of how circadian clock proteins impact diverse aspects of our daily 24-h rhythms and how this intersects with metabolic pathways relevant to disease.

    • Julia Lara
    •  & Brian D. Zoltowski

  • Perspective |

    This historical Perspective on continuous directed evolution focuses on laboratory approaches that enable greater understanding of evolving molecular populations and offer investigators tools to guide the emergence of new biomolecular systems.

    • Mary S. Morrison
    • , Christopher J. Podracky
    •  & David R. Liu

  • News & Views |

    A pair of fluorescent indicator-tagged DNA-duplex scaffolds permit assessments of nitric oxide (NO) production on cell surfaces and in intracellular networks. The application of these nanoprobes indicates formations of local NO signals that might conserve cancer cell integrity.

    • Emrah Eroglu
    • , Thomas Michel
    • , Wolfgang F. Graier
    •  & Roland Malli

  • Article |

    Engineering of yeast transcription factors and design of hybrid DNA promoter elements have resulted in a toolkit for tunable and orthogonal regulation of gene expression in Arabidopsis thaliana and Nicotiana benthamiana plants.

    • Michael S. Belcher
    • , Khanh M. Vuu
    • , Andy Zhou
    • , Nasim Mansoori
    • , Amanda Agosto Ramos
    • , Mitchell G. Thompson
    • , Henrik V. Scheller
    • , Dominique Loqué
    •  & Patrick M. Shih

  • Article |

    Biosensors of guanine exchange factors (GEFs) and red-shifted GTPase biosensors are used to visualize GEF and GTPase activities in the same cells and enable correlation analysis to reveal which GEF–GTPase interactions regulate cell movement.

    • Daniel J. Marston
    • , Marco Vilela
    • , Jaewon Huh
    • , Jinqi Ren
    • , Mihai L. Azoitei
    • , George Glekas
    • , Gaudenz Danuser
    • , John Sondek
    •  & Klaus M. Hahn

  • Article |

    Evolution of a group of plant cellulose synthase-like enzymes into specialized glycosyltransferases in the endoplasmic reticulum membrane confers the ability to glucuronidate triterpenoid saponins and other specialized metabolites.

    • Adam Jozwiak
    • , Prashant D. Sonawane
    • , Sayantan Panda
    • , Constantine Garagounis
    • , Kalliope K. Papadopoulou
    • , Bekele Abebie
    • , Hassan Massalha
    • , Efrat Almekias-Siegl
    • , Tali Scherf
    •  & Asaph Aharoni

  • Article |

    Identification of an improved glucose-6-phosphate dehydrogenase (G6PD) inhibitor G6PDi-1 blocks G6PD activity more robustly than the widely cited antagonist DHEA. G6PDi-1 treatment blocks T cell cytokine production and neutrophil oxidative burst.

    • Jonathan M. Ghergurovich
    • , Juan C. García-Cañaveras
    • , Joshua Wang
    • , Emily Schmidt
    • , Zhaoyue Zhang
    • , Tara TeSlaa
    • , Harshel Patel
    • , Li Chen
    • , Emily C. Britt
    • , Marta Piqueras-Nebot
    • , Mari Carmen Gomez-Cabrera
    • , Agustín Lahoz
    • , Jing Fan
    • , Ulf H. Beier
    • , Hahn Kim
    •  & Joshua D. Rabinowitz

  • Article |

    Structures of 5-lipoxygenase (5-LOX) reveal that NDGA disturbs regions that shield the active site while AKBA binds an allosteric site. NDGA inhibits 5-LOX activity using its redox-active function, while AKBA changes the enzyme’s regiospecificity

    • Nathaniel C. Gilbert
    • , Jana Gerstmeier
    • , Erin E. Schexnaydre
    • , Friedemann Börner
    • , Ulrike Garscha
    • , David B. Neau
    • , Oliver Werz
    •  & Marcia E. Newcomer

  • Article |

    An inhibitor of NAPE-PLD involved in lipid biosynthesis lowers levels of the endocannabinoid anandamide and other N-acylethanolamines in cells and mouse brain and activates the hypothalamus–pituitary–adrenal axis and impaired fear extinction.

    • Elliot D. Mock
    • , Mohammed Mustafa
    • , Ozge Gunduz-Cinar
    • , Resat Cinar
    • , Gavin N. Petrie
    • , Vasudev Kantae
    • , Xinyu Di
    • , Daisuke Ogasawara
    • , Zoltan V. Varga
    • , Janos Paloczi
    • , Cristina Miliano
    • , Giulia Donvito
    • , Annelot C. M. van Esbroeck
    • , Anouk M. F. van der Gracht
    • , Ioli Kotsogianni
    • , Joshua K. Park
    • , Andrea Martella
    • , Tom van der Wel
    • , Marjolein Soethoudt
    • , Ming Jiang
    • , Tiemen J. Wendel
    • , Antonius P. A. Janssen
    • , Alexander T. Bakker
    • , Colleen M. Donovan
    • , Laura I. Castillo
    • , Bogdan I. Florea
    • , Jesse Wat
    • , Helma van den Hurk
    • , Matthias Wittwer
    • , Uwe Grether
    • , Andrew Holmes
    • , Constant A. A. van Boeckel
    • , Thomas Hankemeier
    • , Benjamin F. Cravatt
    • , Matthew W. Buczynski
    • , Matthew N. Hill
    • , Pal Pacher
    • , Aron H. Lichtman
    •  & Mario van der Stelt

  • Article |

    Structural and smFRET analysis reveals the mechanism of opposing catalytic activities of bifunctional Rel enzymes; that is, activation of one of the catalytic domains leads to allosteric inactivation of the other.

    • Hedvig Tamman
    • , Katleen Van Nerom
    • , Hiraku Takada
    • , Niels Vandenberk
    • , Daniel Scholl
    • , Yury Polikanov
    • , Johan Hofkens
    • , Ariel Talavera
    • , Vasili Hauryliuk
    • , Jelle Hendrix
    •  & Abel Garcia-Pino

  • Article |

    Development of BRET sensors for nearly all major G proteins show that GPCR–G-protein coupling ranges from promiscuous to extremely specific, Switch III is a novel site for G-protein engineering, and optimal donor–acceptor positioning is non-obvious.

    • Reid H. J. Olsen
    • , Jeffrey F. DiBerto
    • , Justin G. English
    • , Alexis M. Glaudin
    • , Brian E. Krumm
    • , Samuel T. Slocum
    • , Tao Che
    • , Ariana C. Gavin
    • , John D. McCorvy
    • , Bryan L. Roth
    •  & Ryan T. Strachan

  • News & Views |

    A combination of biochemical and biophysical techniques to document the asymmetric distribution of lipids, with a particular focus on the acyl tails, in mammalian cell membranes show that protein transmembrane domains are similarly asymmetric.

    • Maria Makarova
    •  & Dylan M. Owen

  • Article |

    Lipidomics across the bilayer membrane plus biophysical and fluorescence approaches find asymmetry in phospholipid unsaturation and localization of protein transmembrane domains based on their ability to pack within the different membrane leaflets.

    • J. H. Lorent
    • , K. R. Levental
    • , L. Ganesan
    • , G. Rivera-Longsworth
    • , E. Sezgin
    • , M. Doktorova
    • , E. Lyman
    •  & I. Levental

  • Article |

    Structures of the ketosynthase–chain length factor complex from ishigamide biosynthesis, cross-linked to the acyl carrier protein, reveal the molecular interactions between these domains and how the reaction pocket limits rounds of product extension.

    • Danyao Du
    • , Yohei Katsuyama
    • , Masanobu Horiuchi
    • , Shinya Fushinobu
    • , Aochiu Chen
    • , Tony D. Davis
    • , Michael D. Burkart
    •  & Yasuo Ohnishi

  • Article |

    The authors developed a metabolic labeling method via incorporation of allyl-SAM analogs to profile transcriptome-wide m6A at base resolution, which enables identification of m6A motifs and clustered m6A sites.

    • Xiao Shu
    • , Jie Cao
    • , Mohan Cheng
    • , Siying Xiang
    • , Minsong Gao
    • , Ting Li
    • , Xiner Ying
    • , Fengqin Wang
    • , Yanan Yue
    • , Zhike Lu
    • , Qing Dai
    • , Xiaolong Cui
    • , Lijia Ma
    • , Yizhen Wang
    • , Chuan He
    • , Xinhua Feng
    •  & Jianzhao Liu

  • News & Views |

    Oxygen activation mechanisms catalyzed by flavin cofactors are established for electron transfer (oxidases) and C4a covalent flavin–oxygen adduct formation (oxygen-inserting monooxygenases). A new paradigm for oxygen insertion involving a flavin-N5-aminoperoxide intermediate has now been discovered in select flavin-dependent monooxygenases.

    • David Leys
    •  & Nigel S. Scrutton

  • News & Views |

    Emergence of drug resistance limits the efficacy of HIV drugs, which currently requires life-long administration. In vitro high-throughput screening for competition with a broadly neutralizing antibody of HIV identified a small molecule that extends the strategies for targeting HIV.

    • Shan Su
    •  & Shibo Jiang

  • News & Views |

    The biological function and origin of m6A in DNA have been widely debated. A new study demonstrates that the majority of m6A in DNA originates from RNA catabolism via a nucleotide salvage pathway.

    • Paolo Spingardi
    •  & Skirmantas Kriaucionis

  • Article |

    The side chain interaction within the short disordered segment of yeast prion protein Sup35 could affect the conformation of the main chain, alter the transmission barrier between species and regulate its cross-seeding activity.

    • Toshinobu Shida
    • , Yuji O. Kamatari
    • , Takao Yoda
    • , Yoshiki Yamaguchi
    • , Michael Feig
    • , Yumiko Ohhashi
    • , Yuji Sugita
    • , Kazuo Kuwata
    •  & Motomasa Tanaka

  • Article |

    Domain insertion into the loop region of AcrIIC1 leads to a variant with enhanced inhibitory activity toward Neisseria meningitides Cas9, while structure-guided design turns AcrIIC1 into a potent inhibitor of Staphylococcus aureus Cas9.

    • Jan Mathony
    • , Zander Harteveld
    • , Carolin Schmelas
    • , Julius Upmeier zu Belzen
    • , Sabine Aschenbrenner
    • , Wei Sun
    • , Mareike D. Hoffmann
    • , Christina Stengl
    • , Andreas Scheck
    • , Sandrine Georgeon
    • , Stéphane Rosset
    • , Yanli Wang
    • , Dirk Grimm
    • , Roland Eils
    • , Bruno E. Correia
    •  & Dominik Niopek

  • Article |

    In plants, the cytosolic phenylalanine biosynthetic intermediate phenylpyruvate can serve as an amino acceptor in tryptophan-dependent auxin biosynthesis, thus facilitating crosstalk between these two distinct primary metabolic pathways.

    • Joseph H. Lynch
    • , Yichun Qian
    • , Longyun Guo
    • , Itay Maoz
    • , Xing-Qi Huang
    • , Alekzander S. Garcia
    • , Gordon Louie
    • , Marianne E. Bowman
    • , Joseph P. Noel
    • , John A. Morgan
    •  & Natalia Dudareva

  • Article |

    Systematic characterization of codons using the unnatural base pair dNaM·dTPT3 leads to the discovery of nine new functional codon–anticodon pairs, three of which are shown to be orthogonally decoded by ribosomes and allow incorporation of up to three noncanonical amino acids in Escherichia coli.

    • Emil C. Fischer
    • , Koji Hashimoto
    • , Yorke Zhang
    • , Aaron W. Feldman
    • , Vivian T. Dien
    • , Rebekah J. Karadeema
    • , Ramkrishna Adhikary
    • , Michael P. Ledbetter
    • , Ramanarayanan Krishnamurthy
    •  & Floyd E. Romesberg

  • News & Views |

    Using new letters of DNA to encode information promises to expand the genetic code in a transformative way. A new semisynthetic organism has been created that uses 67 codons for protein biosynthesis, with three new codons based on unnatural nucleotides.

    • Michael C. Jewett
    •  & Michael J. Hammerling

  • Article |

    Drug combinations consisting of two cell death-targeting drugs are enriched for antagonism and ‘single-agent dominance’, where the faster-acting drug suppresses the slower-acting drug due to inhibitory crosstalk between cell death pathways.

    • Ryan Richards
    • , Hannah R. Schwartz
    • , Megan E. Honeywell
    • , Mariah S. Stewart
    • , Peter Cruz-Gordillo
    • , Anna J. Joyce
    • , Benjamin D. Landry
    •  & Michael J. Lee

  • Article |

    A highly selective inhibitor of the DCLK1/2 kinases is used to uncover the consequences of DCLK1 inhibition on viability, phosphosignaling and the transcriptome in patient-derived organoid models of pancreatic ductal adenocarcinoma.

    • Fleur M. Ferguson
    • , Behnam Nabet
    • , Srivatsan Raghavan
    • , Yan Liu
    • , Alan L. Leggett
    • , Miljan Kuljanin
    • , Radha L. Kalekar
    • , Annan Yang
    • , Shuning He
    • , Jinhua Wang
    • , Raymond W. S. Ng
    • , Rita Sulahian
    • , Lianbo Li
    • , Emily J. Poulin
    • , Ling Huang
    • , Jost Koren
    • , Nora Dieguez-Martinez
    • , Sergio Espinosa
    • , Zhiyang Zeng
    • , Cesear R. Corona
    • , James D. Vasta
    • , Ryoma Ohi
    • , Taebo Sim
    • , Nam Doo Kim
    • , Wayne Harshbarger
    • , Jose M. Lizcano
    • , Matthew B. Robers
    • , Senthil Muthaswamy
    • , Charles Y. Lin
    • , A. Thomas Look
    • , Kevin M. Haigis
    • , Joseph D. Mancias
    • , Brian M. Wolpin
    • , Andrew J. Aguirre
    • , William C. Hahn
    • , Kenneth D. Westover
    •  & Nathanael S. Gray

  • Article |

    Synthetic circuit-host interactions affect the performance synthetic biology systems. Analysis of two bi-stable switch circuits reveals differential effects of host growth on circuit memory, which is dependent on the network topology of the circuit.

    • Rong Zhang
    • , Jiao Li
    • , Juan Melendez-Alvarez
    • , Xingwen Chen
    • , Patrick Sochor
    • , Hanah Goetz
    • , Qi Zhang
    • , Tian Ding
    • , Xiao Wang
    •  & Xiao-Jun Tian

  • Article |

    Cell-based phenotypic screening of small-molecule circadian clock modulators identified isoform-selective compounds for highly homologous clock proteins CRY1 and CRY2, revealing a key role of the disordered C-terminal region in compound selectivity.

    • Simon Miller
    • , You Lee Son
    • , Yoshiki Aikawa
    • , Eri Makino
    • , Yoshiko Nagai
    • , Ashutosh Srivastava
    • , Tsuyoshi Oshima
    • , Akiko Sugiyama
    • , Aya Hara
    • , Kazuhiro Abe
    • , Kunio Hirata
    • , Shinya Oishi
    • , Shinya Hagihara
    • , Ayato Sato
    • , Florence Tama
    • , Kenichiro Itami
    • , Steve A. Kay
    • , Megumi Hatori
    •  & Tsuyoshi Hirota

  • Article |

    Nitrile-oxide electrophiles were identified as covalent inhibitors of GPX4 that exhibit increased selectivity and reduced off-target effects relative to chloroacetamide-based inhibitors.

    • John K. Eaton
    • , Laura Furst
    • , Richard A. Ruberto
    • , Dieter Moosmayer
    • , André Hilpmann
    • , Matthew J. Ryan
    • , Katja Zimmermann
    • , Luke L. Cai
    • , Michael Niehues
    • , Volker Badock
    • , Anneke Kramm
    • , Sixun Chen
    • , Roman C. Hillig
    • , Paul A. Clemons
    • , Stefan Gradl
    • , Claire Montagnon
    • , Kiel E. Lazarski
    • , Sven Christian
    • , Besnik Bajrami
    • , Roland Neuhaus
    • , Ashley L. Eheim
    • , Vasanthi S. Viswanathan
    •  & Stuart L. Schreiber

  • News & Views |

    Ferroptosis induced by GPX4 inhibition offers promise for killing drug-resistant cancer cells, yet current GPX4 inhibitors lack selectivity. The discovery of masked nitrile oxide electrophiles as selective prodrug inhibitors of GPX4 points to an attractive path for chemically inducing ferroptosis.

    • Stefan G. Kathman
    •  & Benjamin F. Cravatt

  • Article |

    The authors develop a ribozyme, Tx2.1, that is capable of aminoacylating tRNA with specificity for the anticodon from directed evolution of a T-box riboswitch. Tx2.1 could be used to charge non-natural amino acids in an in vitro translation system.

    • Satoshi Ishida
    • , Naohiro Terasaka
    • , Takayuki Katoh
    •  & Hiroaki Suga

  • Brief Communication |

    A metabolic labeling method reveals that genomic N6-methyl-deoxyadenosine in mammalian cell lines originates not from direct methylation in DNA, but from a misincorporation of the metabolite of ribo-N6-methyladenosine.

    • Michael U. Musheev
    • , Anne Baumgärtner
    • , Laura Krebs
    •  & Christof Niehrs

  • Perspective |

    This Perspective describes the chemical and biophysical principles common to all bifunctional, proximity-inducing small molecules. It also discusses the underappreciated diversity of their chemical structures and biological mechanisms.

    • Christopher J. Gerry
    •  & Stuart L. Schreiber

  • Research Highlight |

    • Yiyun Song

  • News & Views |

    Tyrosine sulfation is a common post-translational modification known to play critical roles in multiple bioprocesses. A cleverly engineered mammalian expanded genetic code now enables the direct co-translational incorporation of tyrosine sulfates into proteins to study their function in cellular contexts.

    • Chang C. Liu

  • Article |

    A cryo-EM structure of potato virus X shows that virions are formed by repeats of segments of coat protein protomers arranged in a left-handed helical structure and reveals details of the RNA–capsid interactions, which shed light on virus assembly.

    • Alessandro Grinzato
    • , Eaazhisai Kandiah
    • , Chiara Lico
    • , Camilla Betti
    • , Selene Baschieri
    •  & Giuseppe Zanotti