Chemical biology articles within Nature Communications

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  • Article
    | Open Access

    Unbiased chemical biology strategies for direct readout of small molecule protein interactomes provide advantages over target-focused approaches. Here, the authors describe the BioTAC system, a network-scale small molecule guided proximity labeling platform, to rapidly identify ligand-target interactomes.

    • Andrew J. Tao
    • , Jiewei Jiang
    •  & Fleur M. Ferguson

  • Article
    | Open Access

    Microbial rhodopsins are major contributors to global light harvesting on Earth, but their role in carbon fixation is unclear. Here, the authors construct an artificial photosynthesis system by combining rhodopsin with an extracellular electron uptake mechanism for photoelectrosynthetic CO2 fixation in Ralstonia eutropha.

    • Weiming Tu
    • , Jiabao Xu
    •  & Wei E. Huang

  • Article
    | Open Access

    Membraneless liquid compartments based on phase-separating biopolymers have been observed in diverse cell types and attributed to weak multivalent interactions predominantly based on intrinsically disordered domains. Here the authors design protein liquid condensates from tunable concatenated coiled-coil dimer modules, unraveling the principles for coexisting condensates, chemical regulation, formation from either one or two polypeptide components in mammalian cells.

    • Maruša Ramšak
    • , Dominique A. Ramirez
    •  & Roman Jerala

  • Article
    | Open Access

    Hemoproteins have recently emerged as promising biocatalysts for carbene transfer reactions but mechanistic understanding of the interplay between productive and unproductive pathways in these processes is limited. Here, the authors use a combination of spectroscopic, crystallographic, and computational tools to elucidate the mechanism of a recently reported myoglobin-catalyzed cyclopropanation reaction with diazoketones.

    • Donggeon Nam
    • , John-Paul Bacik
    •  & Rudi Fasan

  • Article
    | Open Access

    The combination of a covalent electrophile with a peptide or protein-based scaffold enables the targeting of shallow protein surfaces, but the approaches to convert native peptide sequences into covalent binders are missing. Here, the authors report the design of protein-based thiomethacrylate ester electrophiles that can be installed on unprotected peptides and proteins via cysteine side chains and react efficiently and selectively with cysteine and lysine side chains on the target.

    • Ronen Gabizon
    • , Barr Tivon
    •  & Nir London

  • Article
    | Open Access

    Targeted protein degradation (TPD) has emerged as a new paradigm for modulating protein activity. Here, the authors develop bifunctional degraders combining a putative ligand of the autophagy-related LC3 protein with different protein targets, which direct proteins of interest to the proteasome by covalently targeting the DCAF11 E3 ligase substrate receptor.

    • Gang Xue
    • , Jianing Xie
    •  & Herbert Waldmann

  • Article
    | Open Access

    Glycopeptide antibiotics (GPAs) are microbial natural products synthesized by multiple enzymes, including a nonribosomal peptide synthetase for assembly of the peptide core. Here, the authors use computational techniques to infer a gene set for biosynthesis of an ancestral GPA, produce the peptide in a microbial host, and provide insights into the evolution of key enzymatic domains.

    • Mathias H. Hansen
    • , Martina Adamek
    •  & Nadine Ziemert

  • Article
    | Open Access

    NanoLuc luciferase is a popular bioluminescent enzyme, but the molecular details of its mechanism of action on luciferins such as coelenterazine remained elusive. Here the authors use, protein crystal structures and biochemical analyses to provide an atomistic description of its catalytic mechanism and allosteric behaviour.

    • Michal Nemergut
    • , Daniel Pluskal
    •  & Martin Marek

  • Article
    | Open Access

    High binding affinities are usually obtained when ligands are rigidified. Here the authors present flexible peptides binding to Armadillo repeat proteins with femtomolar affinity. They demonstrate that the bound state is characterized by residual dynamics limiting entropic losses upon binding.

    • Stefano Cucuzza
    • , Malgorzata Sitnik
    •  & Oliver Zerbe

  • Article
    | Open Access

    Chemical inducer of dimerization (CID) modules can be used to effectively control biological processes; however, CID modules have been explored primarily in engineering cells for in vitro applications using inducers that have limited clinical utility. Here, the authors identify a CID module with favorable properties to enable rapid translation from in vitro applications to potential use in humans.

    • Stacey E. Chin
    • , Christina Schindler
    •  & Natalie J. Tigue

  • Article
    | Open Access

    Ribosomally synthesized and post-translationally modified peptides (RiPPs) are natural products with significant chemical complexity. Here, the authors identify the dehydrazoles, a class of hypermodified RiPPs with side chain dehydration and backbone heterocyclization, and identify enzymes involved in their biosynthesis and modifications.

    • Zeng-Fei Pei
    • , Lingyang Zhu
    •  & Satish K. Nair

  • Article
    | Open Access

    Vast majority of cellular activities are carried out by protein complexes that assembled dynamically in response to cellular needs and environmental cues. Here, the authors present Slim-TPCA, an effective and readily deployable strategy to unravel the functional roles of protein complexes en masse across various cellular processes.

    • Siyuan Sun
    • , Zhenxiang Zheng
    •  & Chris Soon Heng Tan

  • Article
    | Open Access

    The cis-peptide bond is rare in natural proteins and its impact on protein folding is elusive. Here the authors break the conventional understanding that cis-amide-favoring residues destabilize proteins, elucidate the principles of peptoid cis-trans isomerization in collagen folding, and showcase the use of cis-amide-favoring residues in building programmable and functional peptidomimetics.

    • Rongmao Qiu
    • , Xiaojing Li
    •  & Yang Li

  • Article
    | Open Access

    Stress granules (SGs) are highly dynamic cytoplasmic membraneless organelles that assemble when cells are challenged by stress. Herein, the authors apply a proximity-dependent RNA labeling method, CAP-seq, to comprehensively investigate the content of SG-proximal transcriptome and the dynamic change in SG-proximal transcriptome along the time course of granule assembly and disassembly processes in live mammalian cells.

    • Ziqi Ren
    • , Wei Tang
    •  & Peng Zou

  • Article
    | Open Access

    Recent experimental evidence shows a new type of intrinsic fluorescence in biomolecules void of aromatic chemical compounds whose origin is unclear. Here, the authors use non-adiabatic AIMD simulations to show a potential carbonyl-lock mechanism originating this phenomenon.

    • Gonzalo Díaz Mirón
    • , Jonathan A. Semelak
    •  & Uriel N. Morzan

  • Article
    | Open Access

    Constructing polymer-based mimics on the surface of cells has potential to manipulate cell behavior, but precise control of grafting sites is challenging. Here, the authors report a method for site selected radical polymerization on cell surfaces by metabolic labelling.

    • Yihong Zhong
    • , Lijia Xu
    •  & Huangxian Ju

  • Article
    | Open Access

    Sufficient supply of sulfonate group donor is critical to biomanufacturing of the sulfate containing compounds. Here, the authors engineer two sulfonate group donor regeneration systems, including 3'-phosphoadenosine-5'-phosphosulfate and the newly discovered 5'-phosphosulfate, to boost biosynthesis of sulfated compounds.

    • Ruirui Xu
    • , Weijao Zhang
    •  & Zhen Kang

  • Article
    | Open Access

    Mapping protein turnover dynamics with subcellular precision is crucial for understanding cell physiology and pathology. Here, the authors leveraged APEX2-mediated proximity labeling to develop prox-SILAC methods to profile protein turnover rates in the mitochondria and endoplasmic reticulum.

    • Feng Yuan
    • , Yi Li
    •  & Peng Zou

  • Article
    | Open Access

    Specific modification or functionalization of proteins at the C-terminus is of interest but remains challenging. Here, the authors report an approach for the efficient modification of C-terminus by fusion of the cysteine protease domain (CPD) on the C-terminus of the protein of interest, and subsequent functionalization with amine-containing molecules triggered by InsP6-mediated CPD self-cleavage.

    • Yue Zeng
    • , Wei Shi
    •  & Feng Tang

  • Article
    | Open Access

    Methylation is the dominant modification in mRNA and occurs at a variety of sites. Here, Hartstock et al. show that a clickable analogue of the key cosubstrate S-adenosyl-L-methionine (SAM) can be produced in cells, allowing for identification and mapping of different methylated nucleosides in mRNA.

    • Katja Hartstock
    • , Nadine A. Kueck
    •  & Andrea Rentmeister

  • Article
    | Open Access

    Chemo-activation of mitochondrial ClpP exhibits promising anticancer properties. Here, the authors develop a potent activator ZK53 that is highly selective on human ClpP but inactive toward bacterial ClpP proteins, and show that ZK53 causes cell cycle arrest via ClpP on lung squamous cell carcinoma cells and exhibits therapeutic effects in animal models.

    • Lin-Lin Zhou
    • , Tao Zhang
    •  & Cai-Guang Yang

  • Article
    | Open Access

    The ability to control proteins in cells and animals is important for experimental research and may have therapeutic applications. Here, the authors developed a new set of heterobifunctional small molecules based on the antibiotic trimethoprim that can degrade proteins that are genetically tagged with E. coli dihydrofolate reductase (eDHFR).

    • Jean M. Etersque
    • , Iris K. Lee
    •  & Mark A. Sellmyer

  • Article
    | Open Access

    The rational design and implementation of synthetic mammalian communication systems can unravel fundamental design principles of cell communication circuits and offer a framework for engineering of designer cell consortia with potential applications in cell therapeutics. Here the authors present a synthetic communication platform in mammalian cells based on diffusible dipeptide ligands and synthetic receptors, that is by design highly orthogonal, scalable, and programmable.

    • Anna-Maria Makri Pistikou
    • , Glenn A. O. Cremers
    •  & Tom F. A. de Greef

  • Article
    | Open Access

    Identification of molecules that induce novel interactions between proteins has been limited by the complexity of rationally designing interactions. The authors report a method to discover molecular glue-like “trimerizers” based on α-helically constrained peptides that can co-opt the surfaces of E3 ubiquitin ligases to bind therapeutically important proteins.

    • Olena S. Tokareva
    • , Kunhua Li
    •  & John H. McGee

  • Article
    | Open Access

    This study found that cnidarian animals including corals, anemones and jellyfish share a common mechanism to regulate their association with symbiotic algae. Despite evolving independently, these animals all use the same carbon-nitrogen negative feedback loop for algae control, shedding light on the repeated evolution of these marine symbiotic relationships.

    • Guoxin Cui
    • , Jianing Mi
    •  & Manuel Aranda

  • Article
    | Open Access

    Unnatural base pairing xenonucleic acids (XNAs) can be used to expand life’s alphabet beyond ATGC. Here, authors show strategies for enzymatic synthesis and next-generation nanopore sequencing of XNA base pairs for reading and writing 12-letter DNA (ATGCBSPZXKJV).

    • Hinako Kawabe
    • , Christopher A. Thomas
    •  & Jorge A. Marchand

  • Article
    | Open Access

    Many diseases are driven by the insufficient expression of critical genes, but few technologies are capable of rescuing these endogenous protein levels. Here, Cao et al. present an RNA-based technology that boosts protein production from endogenous mRNAs by upregulating their translation.

    • Yang Cao
    • , Huachun Liu
    •  & Bryan C. Dickinson

  • Article
    | Open Access

    In nature, α-helical peptides adopt right-handed conformations dictated by L-amino acids, but isolating one-handed α-helical peptides composed of only achiral components remains a challenge. Here, the authors achieve this by optical resolution of the corresponding racemic (quasi-)static α-helical peptide with double stapling, which effectively freezes the interconversion between the right-handed (P)- and left-handed (M)-α-helices.

    • Naoki Ousaka
    • , Mark J. MacLachlan
    •  & Shigehisa Akine

  • Article
    | Open Access

    O-acetylation is a common modification of sialic acids. Here, a library of synthetic O-acetylated sialosides made it possible to develop an ion mobility mass spectrometry (IM-MS) approach that can elucidate exact O-acetylation patterns and glycosidic linkage types of sialosides isolated from biological samples.

    • Gaёl M. Vos
    • , Kevin C. Hooijschuur
    •  & Geert-Jan Boons

  • Article
    | Open Access

    Apiosides are plant bioactive natural products containing apiose, but the details of the key apiosylation reaction in their biosynthesis are missing. Here, the authors identify the apiosyltransferase GuApiGT that could efficiently catalyze 2″-O-apiosylation of flavonoid glycosides, solve its crystal structure and obtain mutants with altered sugar selectivity.

    • Hao-Tian Wang
    • , Zi-Long Wang
    •  & Min Ye

  • Article
    | Open Access

    Nonribosomal peptides have diverse bioactivities and can possess unusual moieties at their C-terminus, such as polyamines. In this study, the authors identify a class of dodecapeptides glidonins that feature diverse N-terminal modifications and a uniform putrescine moiety at the C-terminus, elucidate their biosynthesis, and introduce the putrescine into the C-terminus of other nonribosomal peptides.

    • Hanna Chen
    • , Lin Zhong
    •  & Xiaoying Bian

  • Article
    | Open Access

    Heparan sulfate (HS) and chondroitin sulfate (CS) are different glycosaminoglycan chains that are attached to core proteins via the same linker tetrasaccharide, and it was unclear how core proteins are specifically modified with HS or CS. Here, the authors determine that the CS-initiating glycosyltransferase CSGALNACT2 is promiscuous, whereas the HS-initiating glycosyltransferase EXTL3 selects only certain core proteins for modification.

    • Douglas Sammon
    • , Anja Krueger
    •  & Erhard Hohenester

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