Chemical biology

  • Article
    | Open Access

    PARG and ARH3 are the main hydrolases to reverse serine poly(ADP-ribosylation) yet their activities in the process differ. Here, the authors synthesise linear and branched poly(ADP-ribose) molecules, perform structure-function analysis and elucidate the mechanistic differences between PARG and ARH3.

    • Johannes Gregor Matthias Rack
    • , Qiang Liu
    •  & Ivan Ahel
  • Article
    | Open Access

    The authors develop a method to build Manhattan Raman Scattering (MARS) probes based on different core atoms, conjugation ring numbers, and stable isotope substitutions. A quantitative model predicts vibrational frequencies of MARS dyes from structures, which are used in supermultiplexed vibrational imaging.

    • Yupeng Miao
    • , Naixin Qian
    •  & Wei Min
  • Article
    | Open Access

    Aurantinins are polyketides with unusual connectivities and broad antibacterial activity. Here the authors show the biosynthesis of aurantinins, which proceeds via an on-line methyl esterification at the terminus that enables the iterative chain elongations prior to condensation and cyclization.

    • Pengwei Li
    • , Meng Chen
    •  & Yihua Chen
  • Article
    | Open Access

    An efficient chassis for heterologous expression of biosynthetic gene clusters (BGCs) from Gram-negative bacteria is still unavailable. Here, the authors report rational construction of genome-reduced Burkholderials chassis to facilitate production of a class of new compounds by expressing BGC from Chitinimonas koreensis.

    • Jiaqi Liu
    • , Haibo Zhou
    •  & Xiaoying Bian
  • Article
    | Open Access

    Self-assembling peptides have a range of potential applications but developing self-assembling sequences can be challenging. Here, the authors report on a one-bead one-compound combinatorial library where fluorescence is used to detect the potential for self-assembly and identified candidates are evaluated.

    • Pei-Pei Yang
    • , Yi-Jing Li
    •  & Kit S. Lam
  • Article
    | Open Access

    PMOs (phosphorodiamidate morpholino oligomers) have huge potential for antisense therapy but complex and slow synthesis limits application. Here, the authors report the development of automated flow synthesis methods which reduce nucleobase coupling times from hours to minutes removing human errors and allow for high-throughput production.

    • Chengxi Li
    • , Alex J. Callahan
    •  & Bradley L. Pentelute
  • Article
    | Open Access

    Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.

    • Yi Yang
    • , Adam Csakai
    •  & Hang Yin
  • Article
    | Open Access

    Prenylated indole alkaloids contain spirooxindole rings with a 3R or 3S carbon stereocenter, which determines their bioactivities, but the biocatalytic mechanism controlling the 3R- or 3S-spirooxindole formation was unclear. Here, the authors report the biochemical and structural characterization of the oxygenase/semipinacolase CtdE that catalyses the 3S-spirooxindole construction in the biosynthesis of 21R-citrinadin A.

    • Zhiwen Liu
    • , Fanglong Zhao
    •  & Xue Gao
  • Article
    | Open Access

    The intracellular compartment is a crowded environment. Here, the authors use molecular dynamics (MD) simulations to assess inhibitor binding to c-Src kinase and show how ligand binding pathways differ in crowded and dilute protein solutions, highlighting the role of c-Src Tyr82 sidechain.

    • Kento Kasahara
    • , Suyong Re
    •  & Yuji Sugita
  • Article
    | Open Access

    Synchronizing gene expression across eukaryotic communities presents complex challenges. Here the authors construct a compact synthetic system inspired by bacteria response to antibiotics that robustly converts chemical rhythms into synchronized gene expression across populations.

    • Sara Pérez-García
    • , Mario García-Navarrete
    •  & Krzysztof Wabnik
  • Article
    | Open Access

    Filamentous cable bacteria conduct electrical currents over centimeter distances through fibers embedded in their cell envelope. Here, Boschker et al. show that the fibers consist of a conductive core containing nickel proteins that is surrounded by an insulating protein shell.

    • Henricus T. S. Boschker
    • , Perran L. M. Cook
    •  & Filip J. R. Meysman
  • Article
    | Open Access

    Amyloid aggregation of mutant p53 contributes to its loss of tumor suppressor function and oncogenic gain-of-function. Here, the authors use a protein mimetic to abrogate mutant p53 aggregation and rescue p53 function, which inhibits cancer cell proliferation in vitro and halts tumor growth in vivo.

    • L. Palanikumar
    • , Laura Karpauskaite
    •  & Mazin Magzoub
  • Article
    | Open Access

    The chemical processes for the selective incorporation of deuterium into small molecules, of interest to organic and medicinal chemistry, are well established, while the enzymatic methods remain underdeveloped. Here, the authors use an enzymatic approach employing Chlorella variabilis NC64A photodecarboxylase that catalyses decarboxylative deuteration of various carboxylic acids with D2O, and identify enzyme variants that can employ substrates with different chain length acids.

    • Jian Xu
    • , Jiajie Fan
    •  & Qi Wu
  • Article
    | Open Access

    The therapeutic application of small interfering RNA (siRNA) is challenging due to its non-specific targeting and delivery issues. Here, the authors report an endogenous micro-RNA guided and hybridisation chain reaction-promoted siRNA delivery system encapsulated in tumour-derived extracellular vesicles, with cancer-specific activation, and achieve silencing of hypoxia-related genes.

    • Xue Gong
    • , Haizhou Wang
    •  & Fuan Wang
  • Article
    | Open Access

    Small molecules bioactivity descriptors are enriched representations of compounds, reaching beyond chemical structures and capturing their known biological properties. Here the authors present a collection of deep neural networks able to infer bioactivity signatures for any compound of interest, even when little or no experimental information is available for them.

    • Martino Bertoni
    • , Miquel Duran-Frigola
    •  & Patrick Aloy
  • Article
    | Open Access

    The membrane is an integral component of the G protein-coupled receptor signaling machinery. Here authors demonstrate that lipids regulate the signaling efficacy and selectivity of the ghrelin receptor GHSR through specific interactions and bulk effects and observe PIP2 and GM3 induced shifts of the conformational equilibrium of GHSR away from its inactive state.

    • Marjorie Damian
    • , Maxime Louet
    •  & Jean-Louis Banères
  • Review Article
    | Open Access

    Natural products are an important source of bioactive compounds and have versatile applications in different fields, but their discovery is challenging. Here, the authors review the recent developments in genome mining for discovery of natural products, focusing on compounds from unconventional microorganisms and microbiomes.

    • Kirstin Scherlach
    •  & Christian Hertweck
  • Article
    | Open Access

    Current near-IR optogenetic systems to regulate transcription consist of a number of large protein components. Here the authors report a smaller single-component near-IR system, iLight, developed from a bacterial phytochrome that they use to control gene transcription in bacterial and mammalian cells.

    • Andrii A. Kaberniuk
    • , Mikhail Baloban
    •  & Vladislav V. Verkhusha
  • Article
    | Open Access

    Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy.

    • Srijita Bhowmik
    • , Juraj Galeta
    •  & Dalibor Sames
  • Article
    | Open Access

    Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) suffer from limited maturation. Here the authors identify ERRγ agonist as a factor that enhances cardiac morphological, metabolic, contractile and electrical maturation of hiPSC-derived CMs with T-tubule formation.

    • Kenji Miki
    • , Kohei Deguchi
    •  & Yoshinori Yoshida
  • Article
    | Open Access

    Centriole biogenesis begins with self-assembly of SAS-6 proteins into 9-fold symmetrical ring polymers, which then stack into a cartwheel that scaffolds organelle formation. Here, the authors develop monobodies against Chlamydomonas reinhardtii SAS-6 and use X-ray crystallography, atomic force microscopy and cryo-electron microscopy to reveal insights into ring assembly and stacking.

    • Georgios N. Hatzopoulos
    • , Tim Kükenshöner
    •  & Pierre Gönczy
  • Article
    | Open Access

    A large number of mass spectra from different samples have been collected, and to identify small molecules from these spectra, database searches are needed, which is challenging. Here, the authors report molDiscovery, a mass spectral database search method that uses an algorithm to generate mass spectrometry fragmentations and learns a probabilistic model to match small molecules with their mass spectra.

    • Liu Cao
    • , Mustafa Guler
    •  & Hosein Mohimani
  • Article
    | Open Access

    O-GalNAc glycans are essential in many biological and pathological processes, but difficult to access due to their structural complexity and synthetic challenges. Here, the authors report an efficient chemoenzymatic modular assembly strategy to construct structurally diverse O-GalNAc glycans, use the synthesised glycans to generate a synthetic mucin O-glycan microarray and profile binding specificities of glycan-binding proteins.

    • Shuaishuai Wang
    • , Congcong Chen
    •  & Lei Li
  • Article
    | Open Access

    A major goal in Engineering Biology and Materials Science is the development of active, autonomous scaffolds that mimic those present in biological cells. Here the authors report a toolkit for programming the dynamic behaviour of nucleic acid scaffolds in minimal cell-like compartments.

    • Siddharth Agarwal
    • , Melissa A. Klocke
    •  & Elisa Franco
  • Article
    | Open Access

    Despite considerable efforts, quantitative prediction of various molecular properties remains a challenge. Here, the authors propose an algebraic graph-assisted bidirectional transformer, which can incorporate massive unlabeled molecular data into molecular representations via a self-supervised learning strategy and assisted with 3D stereochemical information from graphs.

    • Dong Chen
    • , Kaifu Gao
    •  & Feng Pan
  • Article
    | Open Access

    The transition of prebiotic chemistry to present-day chemistry lasted a very long period of time, but the current laboratory investigations of this process are mostly limited to a couple of days. Here, the authors develop a fully automated robotic prebiotic chemist designed for long-term chemical experiments exploring unconstrained multicomponent reactions, which can run autonomously and uses simple chemical inputs.

    • Silke Asche
    • , Geoffrey J. T. Cooper
    •  & Leroy Cronin
  • Article
    | Open Access

    Fluorogenic RNA aptamers such as Chili display strong fluorescence enhancement upon aptamer–ligand complex formation. Here, the authors provide insights into the mechanism of fluorescence activation of Chili by solving the crystal structures of Chili with its bound positively charged ligands DMHBO+ and DMHBI+, and they reveal that Chili uses an excited state proton transfer mechanism based on time-resolved optical spectroscopy measurements.

    • Mateusz Mieczkowski
    • , Christian Steinmetzger
    •  & Claudia Höbartner
  • Article
    | Open Access

    While the role of specific posttranslational modifications (PTMs) is increasingly well understood for core histones, this is not the case for linker histone H1. Here the authors show that site-specific ubiquitylation of H1 results in distinct interactomes, regulates phase separation, and modulates assembly of chromatosomes.

    • Eva Höllmüller
    • , Simon Geigges
    •  & Florian Stengel
  • Article
    | Open Access

    Substrate channeling can improve biosynthetic efficiency and has been implicated in the reactions of fusicoccadiene synthase. Here, the authors analyze this bifunctional enzyme complex by cryoEM, cross-linking MS and integrative modeling, providing structural insights into how substrate channeling is achieved.

    • Jacque L. Faylo
    • , Trevor van Eeuwen
    •  & David W. Christianson
  • Article
    | Open Access

    Silver (Ag) has been used as an antimicrobial agent since a long time, but its molecular mechanism of action was not elucidated due to technical challenges. Here, the authors develop a mass spectrometric approach to identify the Ag-proteome in Staphylococcus aureus, and capture a molecular snapshot of the dynamic bactericidal mode of action of Ag through targeting multiple biological pathways.

    • Haibo Wang
    • , Minji Wang
    •  & Hongzhe Sun
  • Article
    | Open Access

    Self-assembling peptides (SAPs) can be used to build biomaterials, but genetically encoded SAPs have rarely been used as building blocks in cells. Here, the authors design a SAP that can be genetically fused to target proteins to induce their intracellular clustering and modulate their signaling functions.

    • Takayuki Miki
    • , Taichi Nakai
    •  & Hisakazu Mihara
  • Article
    | Open Access

    Advanced glycation end-products (AGEs), such as methylglyoxal-derived hydroimidazolone isomer (MGH-1), are associated with disease and age-related disorders, and occur spontaneously, so it is unclear why specific protein sites become modified with specific AGEs. Here, the authors use a combinatorial peptide library to determine the chemical features that favour MGH-1 formation for short peptides and demonstrate a key role of tyrosine in this process.

    • Joseph M. McEwen
    • , Sasha Fraser
    •  & Rebecca A. Scheck
  • Article
    | Open Access

    The IDG-DREAM Challenge carried out crowdsourced benchmarking of predictive algorithms for kinase inhibitor activities on unpublished data. This study provides a resource to compare emerging algorithms and prioritize new kinase activities to accelerate drug discovery and repurposing efforts.

    • Anna Cichońska
    • , Balaguru Ravikumar
    •  & Tero Aittokallio
  • Article
    | Open Access

    Recently, a class of non-catechol Dopamine D1 receptor (D1R) selective agonists with novel scaffold and improved pharmacological properties were reported. Here, authors report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 which explains the selectivity of this scaffold for D1R over other aminergic receptors and the mechanism of activating D1R.

    • Bingfa Sun
    • , Dan Feng
    •  & Brian K. Kobilka
  • Article
    | Open Access

    Vibrational energy transfer (VET) is essential for protein function as it is responsible for efficient energy dissipation in reaction sites and is linked to pathways of allosteric communication. Here authors equipped a tryptophan zipper with a VET injector and a VET sensor for femtosecond pump probe experiments to map the VET.

    • Erhan Deniz
    • , Luis Valiño-Borau
    •  & Jens Bredenbeck
  • Article
    | Open Access

    Catalytic enantioselective halocyclization of alkenes is an important bond forming tool and a key step in natural product biosynthesis, but so far no examples of the enzymatic counterpart of this reaction on simple achiral olefins have been reported. Here, the authors describe examples of engineered flavin-dependent halogenases that catalyze halolactonization of olefins with high enantioselectivity and near-native catalytic activity.

    • Dibyendu Mondal
    • , Brian F. Fisher
    •  & Jared C. Lewis
  • Article
    | Open Access

    Current genome mining methods predict many putative non-ribosomal peptides (NRPs) from their corresponding biosynthetic gene clusters, but it remains unclear which of those exist in nature and how to identify their post-assembly modifications. Here, the authors develop NRPminer, a modification-tolerant tool for the discovery of NRPs from large genomic and mass spectrometry datasets, and use it to find 180 NRPs from different environments.

    • Bahar Behsaz
    • , Edna Bode
    •  & Hosein Mohimani
  • Article
    | Open Access

    The circadian clock is an internal mechanism that controls various physiological processes, such as the sleep-wake cycle, but its precise regulation is challenging. Here, the authors develop a visible light-responsive inhibitor of casein kinase I which controls the period and phase of cellular and tissue circadian rhythms in a reversible manner.

    • Dušan Kolarski
    • , Carla Miró-Vinyals
    •  & Ben L. Feringa
  • Article
    | Open Access

    Generating new sensible molecular structures is a key problem in computer aided drug discovery. Here the authors propose a graph-based molecular generative model that outperforms previously proposed graph-based generative models of molecules and performs comparably to several SMILES-based models.

    • Omar Mahmood
    • , Elman Mansimov
    •  & Kyunghyun Cho
  • Article
    | Open Access

    Caerulomycins and collismycins are two types of 2,2’-bipyridine natural products that are biosynthesized via a hybrid NRPS-PKS pathway, but the details of their biosynthesis were unknown. Here, the authors elucidate their biosynthetic pathways, validate the generality of 2,2’-bipyridine formation, and clarify the process for 2,2’-bipyridine furcation.

    • Bo Pang
    • , Rijing Liao
    •  & Wen Liu
  • Article
    | Open Access

    The search for life in the universe is difficult due to issues with defining signatures of living systems. Here, the authors present an approach based on the molecular assembly number and tandem mass spectrometry that allows identification of molecules produced by biological systems, and use it to identify biosignatures from a range of samples, including ones from outer space.

    • Stuart M. Marshall
    • , Cole Mathis
    •  & Leroy Cronin
  • Article
    | Open Access

    The histone methyltransferase ASH1L plays a role in various diseases, including cancer, and has been validated as a therapeutic target; however, no inhibitors of ASH1L have been reported. Here the authors present small molecule inhibitors of ASH1L and demonstrate their on-target activity in leukemia cells and a mouse model of leukemia.

    • David S. Rogawski
    • , Jing Deng
    •  & Jolanta Grembecka
  • Article
    | Open Access

    The poor bench stability of phosphoramidites is a drawback for fast automised chemical oligonucleotide synthesis. Here, the authors report a method for on-demand flow synthesis of phosphoramidites within short reaction times, in near-quantitative yields and sufficient purity for integration with DNA synthesizers.

    • Alexander F. Sandahl
    • , Thuy J. D. Nguyen
    •  & Kurt V. Gothelf