Chemical biology articles within Nature Chemistry

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  • Article |

    Collagen-like peptides can self-assemble into hundreds of closely related triple helices. Now, an algorithm has been developed that predicts the most stable helix and the extent to which it will assemble to the exclusion of the competing helices. This information can help improve the understanding of triple helix design and assembly.

    • Douglas R. Walker
    • , Sarah A. H. Hulgan
    •  & Jeffrey D. Hartgerink

  • Article |

    Constrained molecules typically adopt one major conformation and this limitation prevents the study of other energetically less-favourable conformations. Nevertheless, these alternate structures might prove to be useful and it has now been shown that a dominant rotor method can alter the energetic landscape of peptides to create two-well systems with distinct conformational behaviour.

    • Diego B. Diaz
    • , Solomon D. Appavoo
    •  & Andrei K. Yudin

  • Article |

    A de novo designed zinc-binding protein has been converted into a highly active, stereoselective catalyst for a hetero-Diels–Alder reaction. Design and directed evolution were used to effectively harness Lewis acid catalysis and create an enzyme more proficient than other reported Diels–Alderases.

    • Sophie Basler
    • , Sabine Studer
    •  & Donald Hilvert

  • News & Views |

    Sophisticated drug delivery systems are as essential to modern medicine as drugs themselves. Now, polymer mechanochemistry in sonicated solutions has been used to activate drugs in three different systems. These results offer a promising approach that can be tailored to diverse molecular structures of modern pharmaceuticals.

    • Roman Boulatov

  • News & Views |

    Site-specific attachment of a programmable motif, such as a synthetic nucleic acid tag, on a target protein can facilitate functional studies of proteins in cells or modulation of protein activity. Now, a small genetically encoded peptide enables the templated incorporation of a peptide nucleic acid tag onto membrane proteins in live cells.

    • Jerrin Thomas George
    •  & Sarit S. Agasti

  • Article |

    Polyether ionophores are natural products that display antibacterial activity—but they also show activity against mammalian cells, which has limited their development as clinical antibiotics. Now, a semisynthesis principle of recycling substructures from highly abundant natural polyether ionophores has been used to prepare analogues with enhanced selectivity towards bacterial cells.

    • Shaoquan Lin
    • , Han Liu
    •  & Thomas B. Poulsen

  • Article |

    A method to label membrane proteins with a DNA tag has been developed that enables the selection of DNA-encoded chemical libraries against endogenous membrane proteins on live cells. As a demonstration, a 30-million-compound DNA-encoded chemical library is screened against folate receptor, carbonic anhydrase 12 and epidermal growth factor receptor on live cells.

    • Yiran Huang
    • , Ling Meng
    •  & Xiaoyu Li

  • Article |

    A method for the covalent labelling of proteins by installing a biostable peptide nucleic acid (PNA) tag has now been developed. The PNA label serves as a generic landing platform that enables the recruitment of fluorescent dyes via nucleic acid hybridization and fluorophore removal by toehold-mediated strand displacement. Imaging of cell surface receptors, including internalized receptors, has been demonstrated using this approach.

    • Georgina C. Gavins
    • , Katharina Gröger
    •  & Oliver Seitz

  • Article |

    Bacteria use thioester-bond-containing proteins to covalently bind to host surfaces and withstand large mechanical shocks. Now, thioester bond reactivity has been shown to be force-dependent: forces >35 pN inhibit bond cleavage by primary amine ligands, whereas forces <6 pN enable reversible reformation. This force-modulated thioester bond reactivity could potentially enable bacterial mobility and a route by which they optimize infection.

    • Alvaro Alonso-Caballero
    • , Daniel J. Echelman
    •  & Julio M. Fernandez

  • Review Article |

    Metabolic labelling with unnatural sugars can be used to selectively label tumours with chemical tags. These tags then enable the targeted delivery of molecular cargo including diagnostic and therapeutic agents. This Review Article discusses progress in the design and delivery of unnatural sugars for metabolic labelling of tumour cells and the subsequent development of tumour-targeted chemistry.

    • Hua Wang
    •  & David J. Mooney

  • News & Views |

    Labelling proteins at internal sites holds promise for generating novel protein conjugates in a programmable fashion. Now, a chemoenzymatic approach, dubbed LACE, enables the site-specific modification of recombinant proteins that contain a short genetically encoded tag.

    • Maximilian Fottner
    •  & Kathrin Lang

  • Article |

    Conducting high-resolution, multiplexed imaging in living mammals is challenging because of considerable scattering and autofluorescence in tissue at visible and near-infrared wavelengths. Now, real-time, non-invasive multicolour imaging experiments in live animals have been achieved through the design of optical contrast agents for the shortwave infrared (SWIR, 1,000–2,000 nm) region and the introduction of excitation multiplexing with single-channel SWIR detection.

    • Emily D. Cosco
    • , Anthony L. Spearman
    •  & Ellen M. Sletten

  • Article |

    It is unclear how phospholipid membranes formed on the early Earth, as modern cells synthesize the phospholipid constituents of their membranes enzymatically. Now, a combination of ion pairing and self-assembly has enabled transacylation of lysophospholipids with acyl donors in water, affording a variety of membrane-forming natural diacylphospholipids in high yields.

    • Luping Liu
    • , Yike Zou
    •  & Neal K. Devaraj

  • News & Views |

    Electrophilic groups that undergo sulfur-exchange chemistry with protein nucleophiles can serve as the functional basis of chemical proteomic probes. A new addition to this class, sulfuramidimidoyl fluoride (SAF), which can be included in an array of covalent small molecule probes, exhibits a unique reactivity profile with proteins.

    • Thomas E. Speltz
    •  & Raymond E. Moellering

  • Article |

    A chemoenzymatic method to site-specifically conjugate peptide and protein thioesters to folded proteins at lysine residues has been developed. The method uses a genetically encoded four-residue tag that is recognized by the E2 SUMO-conjugating enzyme Ubc9. This approach enables isopeptide formation with just Ubc9 in a programmable manner and obviates the need for E1 and E3 enzymes.

    • Raphael Hofmann
    • , Gaku Akimoto
    •  & Jeffrey W. Bode

  • Article |

    Latent functional groups—typically unreactive unless activated by protein binding—can provide additional selectivity to covalent drugs. Now, compounds containing the weakly electrophilic sulfuramidimidoyl fluoride group, capable of undergoing sulfur(vi) fluoride exchange, have been used to identify reactive proteins in human cell lysate. This approach has identified a compound that conjugates to and inhibits an important anticancer target.

    • Gabriel J. Brighty
    • , Rachel C. Botham
    •  & Jeffery W. Kelly

  • Article |

    Cyclic β-amino acids can add useful properties to peptides, such as inducing turn structures or providing resistance to proteases. To harness these properties up to ten consecutive cyclic β-amino acids have now been ribosomally incorporated via genetic code reprogramming into a foldamer peptide library that has been screened for potent binders against a protein target, human factor XIIa.

    • Takayuki Katoh
    • , Toru Sengoku
    •  & Hiroaki Suga

  • News & Views |

    Enzymes that methylate using S-adenosyl-l-methionine — nature’s methyliodide — are abundant and often promiscuous; however, a preference for alkylation over methylation has been neither observed in nature nor engineered. Now, carboxymethylation has been demonstrated using engineered methyltransferases.

    • Jennifer N. Andexer
    •  & Andrea Rentmeister

  • Article |

    A series of enzymes that catalyse the formation of strained peptide cyclophanes through a stereospecific C(sp2)–C(sp3) bond have been identified. Crosslinking occurs on three-residue motifs that include tryptophan or phenylalanine to form indole- or phenyl-bridged cyclophanes. These enzymes are widely distributed in nature and represent promising tools for peptide biotechnology.

    • Thi Quynh Ngoc Nguyen
    • , Yi Wei Tooh
    •  & Brandon I. Morinaka

  • Article |

    Artificial intrinsically disordered proteins (A-IDPs) have now been shown to form exclusionary, intracellular droplets that can be designed using simple principles that are based on the aromatic/aliphatic ratio and molecular weight. Droplets that sequester an enzyme and modulate enzyme efficiency on the basis of the molecular weight of the A-IDPs were also engineered using A-IDPs as a minimal condensate scaffold.

    • Michael Dzuricky
    • , Bradley A. Rogers
    •  & Ashutosh Chilkoti

  • Article |

    CD44 is a cell-surface adhesion receptor associated with many biological processes that rely on cellular plasticity. Now, CD44 has been shown to mediate endocytosis of iron-bound hyaluronates. Furthermore, iron catalyses the demethylation of repressive histone marks, thereby unlocking the expression of genes regulating cellular plasticity.

    • Sebastian Müller
    • , Fabien Sindikubwabo
    •  & Raphaël Rodriguez

  • Article |

    The biosynthesis of goadvionins—hybrid lipopeptide antibiotics—is not fully understood. An unusual acyltransferase, GdvG, has now been identified and shown to catalyse a condensation reaction between an acyl-carrier-protein-tethered very-long-chain fatty acid and an eight-residue ribosomally synthesized and post-translationally modified peptide. The position of functional groups in the very-long acyl chain have been determined by tandem mass spectrometry.

    • Ryosuke Kozakai
    • , Takuto Ono
    •  & Hiroyasu Onaka

  • News & Views |

    Tailor-made reverse transcriptases are used in molecular biology and synthetic genetics. However, re-engineering these enzymes to work with non-natural nucleic acids is difficult and requires powerful directed evolution strategies. Now, an adaptable selection approach has been demonstrated for the evolution of new reverse transcriptases.

    • Melanie Henkel
    •  & Andreas Marx

  • Article |

    Visualization of endogenous G-quadruplexes (G4s) in living cells by fluorescence microscopy has been hampered by the high concentrations of G4-binding probes required, which can artificially induce additional G4 formation. Now, a G4-specific fluorescent probe (SiR-PyPDS) has been developed that enables single-molecule and real-time detection of individual G4 structures in living cells without perturbing G4 formation and dynamics.

    • Marco Di Antonio
    • , Aleks Ponjavic
    •  & Shankar Balasubramanian

  • Article |

    Engineering reverse transcriptases for modified or unnatural nucleic acids is challenging, but now a versatile method has been developed that enables the discovery of efficient reverse transcriptases. The method works with a wide range of template structures, including xeno-nucleic acids and can also be used to produce high-fidelity reverse transcriptases for RNA.

    • Gillian Houlihan
    • , Sebastian Arangundy-Franklin
    •  & Philipp Holliger

  • Article |

    Many bacterial pathogens release effector enzymes belonging to the large Fic family, which modify host targets with nucleotide monophosphates. Now, recombinantly produced Fic enzymes have been equipped with synthetic thiol-reactive nucleotide derivatives to make covalent binary probes. The reaction of modified Fic enzymes with their targets permits covalent substrate capture and the structural determination of low-affinity ternary enzyme–nucleotide–substrate complexes.

    • Burak Gulen
    • , Marie Rosselin
    •  & Aymelt Itzen

  • Article |

    The invariable core of a type II polyketide synthase has been characterized using X-ray crystallography, simulations, mutagenesis experiments and functional assays. The characterization of the ternary acyl carrier protein complexes provides a mechanistic understanding of the reactivity and could inform future engineering of this complex biosynthetic machinery.

    • Alois Bräuer
    • , Qiuqin Zhou
    •  & Michael Groll

  • Article |

    The mechanism of nucleation for α-synuclein (α-Syn) aggregation and amyloid formation in Parkinson’s disease is unclear. Now, α-Syn has been shown to undergo liquid–liquid phase separation and a liquid-to-solid-like transition leading to amyloid fibril formation. This raises the possibility that liquid–liquid phase separation is a key pathogenic mechanism behind α-Syn aggregation in Parkinson’s disease.

    • Soumik Ray
    • , Nitu Singh
    •  & Samir K. Maji

  • News & Views |

    Three versatile and mutually orthogonal tRNA/aminoacyl-tRNA synthetase pairs have been developed. Collectively, these pairs enable the site-specific incorporation of three different non-canonical amino acids into a protein that can still be terminated faithfully by a natural stop codon.

    • Christopher D. Reinkemeier
    •  & Edward A. Lemke

  • Article |

    Proteins that interact with histone post-translational modifications have now been identified using an approach based on split-intein mediated histone semisynthesis. Histone modifications and disease-relevant mutations were installed into native chromatin with an adjacent photocross-linker to enable in situ cross-linking. This strategy enabled the determination of chromatin-relevant interactomes and represents a powerful tool for exploring epigenetic regulation and dysregulation at the molecular level.

    • Antony J. Burton
    • , Michael Haugbro
    •  & Tom W. Muir

  • Article |

    Non-canonical amino acids (ncAAs) can be incorporated into proteins in cells using orthogonal aminaocyl–tRNA synthetase/tRNA pairs; the most widely adopted system is based on a pyrrolysyl–tRNA synthetase (PylRS)/tRNA pair. Now, three new PylRS/tRNA pairs have been developed that are mutually orthogonal and can be used together to site-specifically incorporate three distinct ncAAs into a single protein.

    • Daniel L. Dunkelmann
    • , Julian C. W. Willis
    •  & Jason W. Chin

  • Article |

    A naturally occurring stand-alone and intermolecular Diels–Alderase, MaDA, has been identified from Morus alba cell cultures. MaDA is a FAD-dependent enzyme, which catalyses the intermolecular [4+2] cycloaddition via a concerted but asynchronous pericyclic pathway between morachalcone A and a diene generated from moracin C. Characterization revealed that MaDA possesses good substrate promiscuity towards both dienes and dienophiles.

    • Lei Gao
    • , Cong Su
    •  & Xiaoguang Lei

  • Article |

    Aβ42 oligomers are key toxic species associated with protein aggregation; however, the molecular pathways determining the dynamics of oligomer populations have remained unknown. Now, direct measurements of oligomer populations, coupled to theory and computer simulations, define and quantify the dynamics of Aβ42 oligomers formed during amyloid aggregation.

    • Thomas C. T. Michaels
    • , Andela Šarić
    •  & Tuomas P. J. Knowles

  • Article |

    Responsive hydrogels are of interest for a range of potential applications, including microscale soft robotic and biomedical devices. Now, a versatile fabrication approach has been developed to prepare patterned, multi-material and multi-responsive hydrogels. Pre-gel droplets are connected through lipid bilayers in predetermined architectures and photopolymerized to yield continuous hydrogel structures that respond to a variety of stimuli.

    • Florence G. Downs
    • , David J. Lunn
    •  & Hagan Bayley

  • Q&A |

    Yujia Qing, an early-career researcher at the University of Oxford, talks to Nature Chemistry about winning the Dream Chemistry Award 2019, her chemistry dream of ‘Sequencing Life’, and the challenge this represents.

    • Russell Johnson

  • Article |

    A method to fabricate heterotrimeric three-stranded coiled-coil peptide structures has now been developed using coordination around a Pb(ii) centre. The heterotrimeric structures require only three cysteines that bind to Pb(ii) to form a trigonal pyramidal structure, and the formation of an adjacent cavity in which water can hydrogen bond to the cysteine sulfur atoms.

    • Audrey E. Tolbert
    • , Catherine S. Ervin
    •  & Vincent L. Pecoraro

  • Perspective |

    The complexity of proteins has inspired chemists to seek artificial mimetics of protein structure and function. Historically, most such work has focused on analogues of small, isolated segments; however, there is growing interest in mimicry of larger, intact tertiary folds. This Perspective surveys the emerging body of work on these agents, termed ‘proteomimetics’, discusses their construction and outlines some of the remaining challenges.

    • W. Seth Horne
    •  & Tom N. Grossmann

  • Perspective |

    The structures of biologically active natural products have long served as inspiration in drug discovery. This Perspective outlines design principles and connectivity patterns for the de novo combination of natural product-derived fragments. The resulting ‘pseudo-natural products’ retain biological relevance yet exhibit structures and bioactivities not found in the natural products and their derivatives.

    • George Karageorgis
    • , Daniel J. Foley
    •  & Herbert Waldmann

  • Article |

    Screening commercial kinase inhibitors for antibacterial activity identified the anticancer drug sorafenib as a major hit. Subsequent structure–activity optimization created a new antibacterial analogue with high potency against methicillin-resistant Staphylococcus aureus, including challenging persisters and biofilms, as well as demonstrating efficacy in an in vivo mouse model. The mode of action involves stimulation of protein secretion and inhibition of menaquinone biosynthesis.

    • Philipp Le
    • , Elena Kunold
    •  & Stephan A. Sieber

  • Article |

    It is difficult to develop suitable fluorescent probes for live-cell nanoscopy, but a general strategy is now reported that can transform regular fluorophores into fluorogenic probes with excellent cell permeability and low unspecific background signals. Using this approach, probes in a variety of colours were developed for different cellular targets and used for wash-free, multicolour, live-cell confocal and STED microscopy.

    • Lu Wang
    • , Mai Tran
    •  & Kai Johnsson

  • News & Views |

    Biological receptors distinguish between S- and R-enantiomers and these subtle differences in chirality can lead to vastly different protein affinities. Now, a proteomics approach has been developed that capitalizes on chirality to map enantiomeric probe pairs and provides a rapid and global view of protein ligandability within the cell.

    • Yuka Amako
    •  & Christina M. Woo

  • News & Views |

    Flavin-dependent halogenases catalyse the regioselective formation of carbon–chlorine and carbon–bromine bonds using oxygen and inorganic halide salts. Now, genome mining has led to the discovery of a previously unknown viral halogenase that catalyses the iodination of arenes, thereby providing a rare biocatalytic tool for the formation of carbon–iodine bonds.

    • Christian Schnepel
    •  & Nicholas J. Turner

  • Article |

    A set of enantioprobes—photoreactive, clickable fragment pairs differing only in absolute stereochemistry—have been used to provide a robust and streamlined chemical proteomic map of small-molecule/protein interactions in human cells. More than 170 stereoselective fragment–protein interactions were discovered and shown to occur at functional sites on proteins from diverse classes.

    • Yujia Wang
    • , Melissa M. Dix
    •  & Benjamin F. Cravatt

  • News & Views |

    The biosynthetic pathway that produces the structurally uncharacterized gut bacterial genotoxin colibactin can produce unstable, macrocyclic products; however, the extent to which these structures contribute to colibactin’s biological activities is not yet fully understood. Now, two recent studies have provided new insights and reached distinct conclusions regarding their potential mechanisms of action and relevance for genotoxicity.

    • Erik S. Carlson
    •  & Emily P. Balskus

  • Article |

    Enacyloxin IIa is an antibiotic, assembled by a modular polyketide synthase, with promising activity against the Gram-negative bacterium Acinetobacter baumannii. Now, it has been shown that the enacyloxin IIa polyketide chain is released via transfer to a separately encoded carrier protein by a non-elongating ketosynthase domain, followed by condensation with 3,4-dihydroxycyclohexane carboxylic acid by a non-ribosomal peptide synthetase condensation domain.

    • Joleen Masschelein
    • , Paulina K. Sydor
    •  & Gregory L. Challis

  • Article |

    The antibiotic enacyloxin IIa is assembled by a modular polyketide synthase, and released from it by condensation of the enacyloxin acyl chain with 3,4-dihydroxycyclohexane carboxylic acid. A multipronged approach shows the structural basis for recognition between the peptidyl carrier protein domain that bears the acyl chain and the non-ribosomal peptide synthetase condensation domain that ligates it with the carboxylic acid.

    • Simone Kosol
    • , Angelo Gallo
    •  & Józef R. Lewandowski

  • Article |

    Precolibactin 886 is a complex microbiome-derived metabolite implicated in colorectal cancer and produced by the clb gene cluster. A chemical synthesis and analysis of precolibactin 886 is reported which shows that its biosynthetic precursor degrades to other known clb metabolites. The data also provide insights into the structures and reactivity of advanced clb products.

    • Alan R. Healy
    • , Kevin M. Wernke
    •  & Seth B. Herzon

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