Biological sciences articles within Nature Chemistry

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  • News & Views |

    Designing membrane proteins that function as ion channels is challenging. Now, peptides that self-assemble into water-soluble α-helical barrels have been repurposed to form ion channels in membranes by lining the interior with polar residues and the exterior with hydrophobic ones.

    • Giovanna Ghirlanda

  • News & Views |

    Nucleic acids can adopt G-quadruplex folds whose cellular roles remain poorly defined. Synthesis of new probes has now enabled the identification of human proteins that interact with G-quadruplexes. This could provide new clues to decipher the function of these curious folds.

    • Aaron M. Fleming
    •  & Cynthia J. Burrows

  • Article
    | Open Access

    DNA–protein interactions are essential to genome function, but they are challenging to map in a cellular environment. Now, a chemical proteomics approach, which uses DNA G-quadruplex-specific ligands containing a photocrosslinking motif, has enabled the systematic identification of DNA G-quadruplex-binding proteins in live cells.

    • Xiaoyun Zhang
    • , Jochen Spiegel
    •  & Shankar Balasubramanian

  • Article |

    The molybdenum cofactor (Moco) is found in the active site of numerous enzymes, but the mechanism of molybdate insertion is not clear. Now, the mechanism of the final maturation step, in which adenylated molybdopterin and molybdate are the substrates, has been revealed. X-ray crystallography of an Mo-insertase identified adenylated Moco as an unexpected intermediate in this reaction sequence.

    • Corinna Probst
    • , Jing Yang
    •  & Tobias Kruse

  • Article |

    Zinc fluxes have now been shown to be essential in the fertilization of amphibian eggs. Furthermore, manganese(ii), which is initially bound to low-molecular-weight carboxylates, is stored and released with zinc from cortical vesicles following fertilization. This rapid metal ion release blocks the otherwise fatal entry of a second sperm.

    • John F. Seeler
    • , Ajay Sharma
    •  & Thomas V. O’Halloran

  • Article |

    Prodrugs offer one route to treat cancer, but they require activation once they have been delivered to the tumour. Now, a simultaneous chemo-radiotherapy strategy has been demonstrated in mice that uses gamma or X-ray irradiation to locally activate an anticancer prodrug.

    • Jin Geng
    • , Yichuan Zhang
    •  & Mark Bradley

  • News & Views |

    DNA-encoded libraries are a powerful tool to identify hit compounds for drug discovery. Now, two papers have reported new advances in this technology. One paper reports a method to screen for binders inside a living cell, and the other investigates the effects of stereo- and regiochemistry on ligand discovery.

    • Minsoo Song
    •  & Gil Tae Hwang

  • News & Views |

    The cell membrane acts as a border that restricts uptake of extracellular proteins. Now, peptide chemists have developed two new approaches for transporting functional and biologically relevant proteins across the cellular border by anchoring cyclic polyarginine peptides on the cell membrane.

    • Jan Vincent V. Arafiles
    •  & Shiroh Futaki

  • News & Views |

    Phage display enables screening of billions of peptides comprised mainly of natural amino acids. Now, a method to attach and encode a range of structurally diverse compounds has been reported. This method can expand the chemical space covered by phage display peptide libraries.

    • Christian Heinis

  • Article |

    Although iron–sulfur cofactors are known to carry out biological nitrogen fixation, how these clusters bind dinitrogen remains poorly understood. Now, a dinitrogen complex of a synthetic iron–sulfur cluster has been characterized, and electronic cooperation in the cluster has been shown to result in strong N–N bond activation.

    • Alex McSkimming
    •  & Daniel L. M. Suess

  • Article |

    Simulations of the SARS-CoV-2 proteome that include over 0.1 s of aggregate data are reported. Spike opening was observed, revealing cryptic epitopes that differ between variants, explaining differential interactions with antibodies and receptors that determine pathogenicity. The cryptic pockets described provide new targets for antivirals and a wealth of mechanistic insight.

    • Maxwell I. Zimmerman
    • , Justin R. Porter
    •  & Gregory R. Bowman

  • Article |

    RNA origami can be used for the modular design of RNA nanoscaffolds but can be challenging to design. Newly developed computer-aided design software has now been shown to improve the folding yield of kilobase-sized RNA origami. These structures fold from a single strand during transcription by an RNA polymerase, and are able to position small molecules and protein components with nanoscale precision.

    • Cody Geary
    • , Guido Grossi
    •  & Ebbe S. Andersen

  • Article |

    The de novo design of functional membrane proteins is a formidable challenge. Now, water-soluble peptides have been designed that assemble into α-helical barrels with accessible, polar and hydrated central channels. Insights from these structures have been used to produce stable membrane-spanning, cation-selective channels.

    • Alistair J. Scott
    • , Ai Niitsu
    •  & Derek N. Woolfson

  • News & Views |

    Although critically important for protein function, post-translational modifications are complex and notoriously difficult to study. Now, the effects of O-GlcNAcylation on chaperone activity and the accompanying inhibition of amyloid fibril formation have been revealed, potentially yielding new routes to combat neurodegeneration.

    • Sheena E. Radford
    •  & Theodoros K. Karamanos

  • News & Views |

    The continuous monitoring of proteins is a current challenge in medical diagnostics. A new electrochemical approach aiming to address this has been described. The method uses antibodies as a recognition element to achieve the real-time measurement of proteins in saliva in the mouth.

    • Kevin J. Cash
    •  & Kevin W. Plaxco

  • Article |

    Voltage imaging is a powerful technique for studying electrical signalling in neurons. A palette of bright and sensitive voltage indicators has now been developed via enzyme-mediated ligation and Diels–Alder cycloaddition. Among these, a far-red indicator faithfully reports neuronal action potential dynamics with an excitation spectrum orthogonal to optogenetic actuators and green/red-emitting biosensors.

    • Shuzhang Liu
    • , Chang Lin
    •  & Peng Zou

  • Article |

    Robust delivery of proteins into cells is challenging, but it has now been shown that by conjugating arginine-rich cell-penetrating peptides to the surface of cells, proteins containing a cell-penetrating peptide can be delivered efficiently into them. Using a thiol-reactive cell-penetrating peptide enables thiol-containing proteins to be delivered by simple co-incubation.

    • Anselm F. L. Schneider
    • , Marina Kithil
    •  & Christian P. R. Hackenberger

  • News & Views |

    The therapeutic applications of DNAzymes are limited because of their low effectiveness in vivo. Now, a promising approach for constructing DNAzymes that show high gene-silencing efficiency in mammalian cells has been developed. This approach incorporates chemical modifications into an existing DNAzyme scaffold.

    • Yifei Zhou
    •  & Chuanzheng Zhou

  • Article |

    Small liposomes of uniform sizes are valuable tools for studying membrane biology and developing drug-delivery vehicles. Now, a DNA-assisted sorting technique has been shown to produce multiple species of monodispersed liposomes with mean diameters below 150 nm in a scalable manner. This approach has enabled the high-resolution analyses of curvature-dependent membrane protein activities.

    • Yang Yang
    • , Zhenyong Wu
    •  & Chenxiang Lin

  • Article |

    RNA-cleaving DNA enzymes (DNAzymes) have the potential to function as therapeutic agents by silencing the expression of disease-associated proteins. Xeno-nucleic acids were used to improve the catalytic activity and biological stability of a highly evolved DNAzyme known as 10–23. The enzyme exhibits a robust multiple-turnover activity in cultured mammalian cells.

    • Yajun Wang
    • , Kim Nguyen
    •  & John C. Chaput

  • Article |

    The specificity of human and animal viruses that engage with O-acetylated sialic acids has now been probed using a collection of O-acetylated sialoglycans obtained by diversification of trisaccharide precursors with viral haemagglutinin–esterases. The results revealed host-specific patterns of receptor recognition and showed that human respiratory viruses uniquely employ 9-O-acetylated α2,8-linked disialosides as receptors.

    • Zeshi Li
    • , Yifei Lang
    •  & Geert-Jan Boons

  • Article |

    The post-translational modification O-GlcNAc on amyloid-forming proteins can inhibit their aggregation. Now, it has been shown that O-GlcNAc modification of small heat shock proteins HSP27, αA- and αB-crystallin can increase their anti-amyloid activity and block the amyloid formation of both α-synuclein and Aβ(1–42). A mechanism for this protective effect based on decreased physical interactions is also proposed.

    • Aaron T. Balana
    • , Paul M. Levine
    •  & Matthew R. Pratt

  • 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

  • Article |

    High-throughput biocatalytic screening and metagenomics have been used to discover over 300 imine reductases (IREDs) and subsequently produce a sequence-diverse panel of IREDs suitable for optimizing the synthesis of chiral amines. Additional characterization identified biocatalysts that accommodate structurally demanding amines and ketones for enzymatic reductive aminations.

    • James R. Marshall
    • , Peiyuan Yao
    •  & Nicholas J. Turner

  • 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 |

    134Ce and 134La have great potential as companion diagnostic isotopes for radiotherapeutics labelled with α-emitting 225Ac and 227Th. Now, by controlling the CeIII/CeIV redox couple, the large-scale production, purification and characterization of 134Ce- and 134La-based radiolabels has been achieved and their use for in vivo positron emission tomography is demonstrated.

    • Tyler A. Bailey
    • , Veronika Mocko
    •  & Rebecca J. Abergel

  • 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

  • Article |

    The self-assembly of haemoglobin-containing erythrocyte membrane fragments onto the surface of preformed coacervates has been used to make hybrid synthetic cells that can initiate nitric-oxide-induced vasodilation. These synthetic cells encapsulate enzymes that generate a flux of nitric oxide, as well as exhibiting high haemocompatibility and increased blood circulation times.

    • Songyang Liu
    • , Yanwen Zhang
    •  & Stephen Mann

  • Editorial |

    It is far from certain how simple chemical reactions became interconnected networks that gave rise to life on early Earth. Exploring the possible ways in which this could have occurred is an active area of research and a collection of articles in this issue consider what chemical steps may have been taken on the path towards life as we know it today.

  • Article |

    Life requires a constant supply of energy, but the energy sources that drove the transition from prebiotic chemistry to biochemistry on the early Earth are unknown. Now, a potentially prebiotic chemical activating reagent has been shown to enable the synthesis, in aqueous conditions and catalysed by small molecules, of peptides, peptidyl–RNAs, RNA oligomers and primordial phospholipids.

    • Ziwei Liu
    • , Long-Fei Wu
    •  & John D. Sutherland

  • 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 |

    Metal-catalysed prebiotic reactions have been proposed as forerunners of modern metabolism. Now, an abiotic pathway resembling the reverse tricarboxylic acid cycle has been shown to proceed without metal catalysis. The reaction of glyoxylate and pyruvate produces a series of α-ketoacid tricarboxylic acid analogues, and provides a route to generate α-amino acids by transamination.

    • R. Trent Stubbs
    • , Mahipal Yadav
    •  & Greg Springsteen

  • 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 |

    Despite the fundamental role of ATPase in catalysing ATP hydrolysis, the structural and energetic aspects of this process are not fully understood. Coarse-grained computational models have now been used to calculate the free-energy surfaces of different types of ATPases. The catalytic dwell is shown not to be crucial for movement against applied torque.

    • Chen Bai
    • , Mojgan Asadi
    •  & Arieh Warshel

  • 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

  • Article |

    A selection-based screen has now revealed preferences in small-molecule chemotypes that bind RNA as well as preferences in the RNA motifs that bind small molecules. Analysis of these data enabled the design of a small molecule that selectively binds a non-coding microRNA and upregulates expression of vascular endothelial growth factor A.

    • Hafeez S. Haniff
    • , Laurent Knerr
    •  & Matthew D. Disney

  • 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

  • News & Views |

    An approach to design artificial intrinsically disordered proteins using a short peptide as a repeating unit has been reported. This design enables the phase behaviour of the protein to be finely tuned inside cells and enabled the formation of phase-separated condensates that can modulate chemical reactions.

    • Soumik Ray
    •  & Samir K. Maji

  • 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 |

    Class II terpene cyclases convert simple linear substrates into complex polycyclic compounds, which typically requires multiple protein domains. Now, a single-domain class II cyclase, a cyanobacterial merosterolic acid synthase, has been identified and characterized. High-resolution X-ray crystal structures provide detailed insights into how a minimalistic enzyme accomplishes this complex cyclization process.

    • Philipp Moosmann
    • , Felix Ecker
    •  & Jörn Piel

  • 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 |

    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

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