Chemical biology articles within Nature Chemistry

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  • Article
    | Open Access

    Ribosomal incorporation of non-α-amino acid monomers into proteins is largely restricted to in vitro translation. Now, pyrrolysyl-transfer RNA synthetase variants have been shown to acylate tRNAs with α-thio acids, malonic acids, and N-formyl amino acids. This work represents a key step towards the programmed ribosomal synthesis of sequence-defined non-protein polymers in cellulo.

    • Riley Fricke
    • , Cameron V. Swenson
    •  & Alanna Schepartz

  • News & Views |

    Constructing aptamers with desired target-binding affinities may lead to new applications but is challenging. Now, a new method using a high-dimensional microfluidic approach enables quantitative isolation of aptamers with programable binding affinities.

    • Ping Song
    •  & Chunhai Fan

  • Article |

    Cellular membranes contain numerous lipids, and efforts to understand the biological functions of individual lipids demand approaches for controlled modulation of membrane composition in situ. Now, click chemistry-based directed evolution of a microbial phospholipase within mammalian cells affords an editor for optogenetic, targeted modification of phospholipids in cell membranes.

    • Reika Tei
    • , Saket R. Bagde
    •  & Jeremy M. Baskin

  • Article
    | Open Access

    In vitro screening of a ribosomally synthesized macrocyclic peptide library containing cyclic γ2,4-amino acids (cγAA) afforded the discovery of potent inhibitors of the SARS-CoV-2 main protease (Mpro). A co-crystal structure revealed the contribution of this cγAA to Mpro binding and the proteolytic stability of these macrocycles.

    • Takashi Miura
    • , Tika R. Malla
    •  & Hiroaki Suga

  • Article |

    Precise analysis of DNA–protein interactions can help to better understand various biological processes. Now, the ‘light-induced lysine (K) enabled crosslinking’ strategy (shortened to ‘LIKE-XL’) has been developed for spatiotemporal and global profiling of DNA–protein interactions, affording the discovery of low-affinity interactions between transcription factors and DNA using sequence-specific DNA baits.

    • An-Di Guo
    • , Ke-Nian Yan
    •  & Xiao-Hua Chen

  • Article |

    The inability to access well-defined polysaccharides in sufficient quantities has hampered our understanding of their structure–function relationships. Now it has been shown that native precision polysaccharides can be readily prepared via living polymerization of 1,6-anhydrosugars. The obtained polymers display excellent chemical recyclability, suggesting their potential utility as a class of sustainable materials.

    • Lianqian Wu
    • , Zefeng Zhou
    •  & Jia Niu

  • Article |

    Techniques to specifically modulate protein activity are needed to interrogate spatial effects in cellular processes. A genetically encoded method for site-specific protein–protein conjugation based on a photoclick chemical reaction has now been developed. This method permits rapid and irreversible reassembly of bioactive proteins from non-functional split fragment pairs with full spatiotemporal control in solution, biomaterials and living mammalian cells.

    • Emily R. Ruskowitz
    • , Brizzia G. Munoz-Robles
    •  & Cole A. DeForest

  • Research Briefing |

    Nanomachines are central to life and are becoming an important part of self-regulated nanotechnologies. Inspired by natural self-assembled nanosystems, it has been shown that artificial nanosystems can evolve and adopt regulatory functions upon fragmentation of their structures into multiple components that reassemble to form the same nanostructure.

  • Article |

    A nanopore framework has been developed to reveal the crosstalk effect on the renin–angiotensin system. By reading the single-amino-acid differences in angiotensin peptides with high accuracy and high efficiency, the selective inhibition of angiotensin-converting enzyme by angiotensin-converting enzyme 2 was revealed. This activity was shown to be suppressed by the spike protein of SARS-CoV-2.

    • Jie Jiang
    • , Meng-Yin Li
    •  & Yi-Tao Long

  • News & Views |

    Post-translational modification of proteins is widely used for studying biological processes; however, competing reactions can provide numerous challenges. Now, a visible-light photocatalytic diselenide contraction enables the highly chemoselective functionalization of selenopeptides and proteins under mild conditions.

    • Nicholas A. Fitzpatrick
    •  & Patricia Z. Musacchio

  • Article |

    Cycloaddition reactions are among the most useful reactions in chemical synthesis, but biosynthetic enzymes with 2 + 2 cyclase activity have yet to be observed. Now it is shown that a β-barrel-fold protein catalyses competitive 2 + 2 and 4 + 2 cycloaddition reactions. This protein can be engineered to preferentially produce the exo-2 + 2, exo-4 + 2 or endo-4 + 2 product.

    • Hongbo Wang
    • , Yike Zou
    •  & K. N. Houk

  • Article |

    A Diels–Alderase that catalyses the inherently disfavoured cycloaddition and forms a bicyclo[2.2.2]diazaoctane scaffold with a strict α-anti-selectivity has now been discovered. This Diels–Alderase, called CtdP, is an NmrA-like protein. Isotopic labelling, structural biology and computational studies reveal that the CtdP-catalysed Diels–Alder reaction involves a NADP+/NADPH-dependent redox mechanism.

    • Zhiwen Liu
    • , Sebastian Rivera
    •  & Xue Gao

  • News & Views |

    Ribosomes cannot synthesize peptides using hydroxy acids to replace canonical amino acids as no codons encode hydroxy acid building blocks. Now, this challenge has been addressed by rewriting the genetic code, enabling the direct cellular biosynthesis of non-natural depsipeptides containing non-canonical amino acids.

    • Jian Li

  • News & Views |

    Interactions between proteins and non-proteinaceous biopolymers are essential for life; however, many methods used to characterize these interactions lack precision and display significant biases. Now, a genetically encoded method employing sulfur(vi) fluoride exchange (SuFEx)-based chemical crosslinking has been developed for capturing and analysing protein–RNA and protein–carbohydrate interactions in vivo.

    • Christopher P. Watkins
    •  & Ryan A. Flynn

  • Article |

    The complementarity of the two strands in the DNA double helix provides a mechanism for the storage and processing of genetic information. Now, an alternative ‘strand commutation’ mechanism of data processing with DNA/RNA has been revealed based on the reversible low-affinity interactions of essentially non-complementary nucleic acids.

    • Maxim P. Nikitin

  • Article
    | Open Access

    Macrocyclic peptides can be genetically encoded and synthesized in cells; however, the programmable diversity is limited. Now, macrocycles containing two non-canonical amino acids have been genetically encoded and synthesized in codon-reassigned Syn61Δ3 cells. Incorporating diverse hydroxy acids in Syn61Δ3 cells enables the synthesis of non-natural depsipeptides containing either one or two ester bonds.

    • Martin Spinck
    • , Carlos Piedrafita
    •  & Jason W. Chin

  • Article |

    Enzymes with identical sequences of amino acids can display varying activities when encoded with mRNA with different properties, but why this is the case has been a mystery. Now, it has been shown that synonymous mutations in mRNA alter the partitioning of proteins into long-lived soluble misfolded states with varying activities.

    • Yang Jiang
    • , Syam Sundar Neti
    •  & Edward P. O’Brien

  • Article
    | Open Access

    Native mass spectrometry has been used to interrogate both biased signalling and allosteric modulation of the β1-adrenergic receptor. Simultaneously capturing the effects of ligand binding and receptor coupling to different G proteins has enabled the relative importance of specific interactions to be investigated.

    • Hsin-Yung Yen
    • , Idlir Liko
    •  & Carol V. Robinson

  • Article
    | Open Access

    The circadian rhythm generates out-of-equilibrium metabolite oscillations controlled by feedback loops under light/dark cycles. Now, it has been shown that these life-like properties can emerge from a non-equilibrium nanosystem comprising a binary population of enzyme-containing polymersomes capable of light-gated chemical communication, controllable feedback and coupling to macroscopic oscillations.

    • Omar Rifaie-Graham
    • , Jonathan Yeow
    •  & Molly M. Stevens

  • Article |

    Despite recent advances in engineering of in vitro translation systems, direct ribosomal incorporation of hydroxyhydrocarbon moieties—which can endow peptides with unique biochemical/folding properties—remains challenging. Now, incorporation of translation-compatible azide/hydroxy acids and their post-translational tandem backbone-acyl shifts have enabled in vitro ribosomal synthesis of peptides containing various hydroxyhydrocarbon units.

    • Tomohiro Kuroda
    • , Yichao Huang
    •  & Hiroaki Suga

  • Article |

    Enteropeptins are peptide natural products produced by the gut microbe Enterococcus cecorum. Now, the structure, biosynthesis and function of enteropeptins have been determined. After ribosomal biosynthesis, enteropeptins are post-translationally modified in three reactions carried out by a radical S-adenosylmethionine enzyme, an Mn2+-dependent arginase, and an Fe–S-containing methyltransferase, respectively, to form the N-methylornithine-containing peptide natural products.

    • Kenzie A. Clark
    • , Brett C. Covington
    •  & Mohammad R. Seyedsayamdost

  • Article |

    Creating hierarchical synthetic materials that can modulate microbial communities remains a great challenge due to the complex interactions between microbiota and their colonized environments. Now, a soil-inspired chemical system that responds to chemical, optical and mechanical stimuli has been developed. The soil-inspired chemical system can enhance microbial cultures and biofuel production, enrich gut bacterial diversity and alleviate ulcerative colitis symptoms.

    • Yiliang Lin
    • , Xiang Gao
    •  & Bozhi Tian

  • News & Views |

    DNA nanotechnology and synthetic biology both aim to expand the range of dynamic behaviours exhibited by rationally programmed biomolecules. Now, the programmability of synthetic transcriptional circuits has been improved to enable synthesis of dynamic biomolecular circuits with unmatched complexity.

    • Jongmin Kim
    •  & Friedrich C. Simmel

  • Article |

    Sterically demanding 2′-modified nucleotides used in antisense therapeutics have thus far been challenging to synthesise enzymatically. Now, it has been shown that mutation of two gatekeeper residues in an archaeal DNA polymerase unlocks efficient synthesis of the modified nucleic acid oligomers 2′-O-methyl-RNA and 2′-O-(2-methoxyethyl)-RNA and enables the evolution of 2′-O-methyl-RNA enzymes.

    • Niklas Freund
    • , Alexander I. Taylor
    •  & Philipp Holliger

  • Article |

    Protein–carbohydrate interactions remain challenging to study due to their low binding affinity and non-covalent nature. Now, a genetically encoded bioreactive unnatural amino acid containing sulfonyl fluoride has been shown to crosslink a protein with its bound glycan, offering a solution to probe and exploit protein–carbohydrate interactions.

    • Shanshan Li
    • , Nanxi Wang
    •  & Lei Wang

  • Article |

    Technologies for profiling biological environments with high spatiotemporal resolution are in demand to enable the discovery of new targets for addressing unmet clinical needs. Now, a deep red light-mediated photocatalytic strategy for the targeted activation of aryl azides has been developed. This platform enables mapping of protein microenvironments in physiologically relevant systems.

    • Nicholas Eng Soon Tay
    • , Keun Ah Ryu
    •  & Tomislav Rovis

  • Article |

    Protein–RNA interactions regulate RNA fate and function, and are generally non-covalent and reversible. Genetically introducing a latent bioreactive amino acid into a protein is now shown to enable the protein to covalently crosslink a bound RNA molecule in vivo. This method offers innovative avenues for developing protein–RNA research and applications.

    • Wei Sun
    • , Nanxi Wang
    •  & Lei Wang

  • News & Views |

    Quantitatively studying the partitioning of biomolecules and reaction equilibria in cellular systems is an enormous challenge. Now, a multiphase coacervate model system provides insight into this complex biological problem, illustrating how coexisting phases influence RNA partitioning and duplex dissociation.

    • Shuqi Wu
    •  & Liangfei Tian

  • Article |

    The total synthesis and complete stereochemical assignment of the cyclic peptide natural product SR-A3—which has potential as a cancer therapeutic—has now been reported. Single-molecule biophysical and cellular experiments reveal a crucial, stereospecific role for a side-chain hydroxyl in SR-A3, which confers enhanced target residence time and efficacy in a mouse tumour model.

    • Hao-Yuan Wang
    • , Haojun Yang
    •  & Jack Taunton

  • Article |

    Oligonucleotide catalysts such as ribozymes and DNAzymes can cleave RNA efficiently and specifically but are typically dependent on high concentrations of divalent cations, limiting their biological applications. A modular XNAzyme catalyst composed of 2′-deoxy-2′-fluoro-β-d-arabino nucleic acid (FANA) has now been developed that can cleave long (>5 kb), highly structured mRNAs under physiological conditions and enables allele-specific catalytic RNA knockdown inside cells.

    • Alexander I. Taylor
    • , Christopher J. K. Wan
    •  & Philipp Holliger

  • Article |

    The biosynthesis of fuscimiditide, a ribosomally synthesized post-translationally modified peptide, has now been reported. Heterologous expression and analysis of fuscimiditide showed it contained two side-chain–side-chain ester linkages and an aspartimide in its backbone. The aspartimide moiety is unexpectedly stable, suggesting this structure is the intended natural product.

    • Hader E. Elashal
    • , Joseph D. Koos
    •  & A. James Link

  • Article |

    The β1-adrenergic receptor (β1AR) contains empty cavities in its preactive conformation, which disappear in the active one. Now, using X-ray crystallography of xenon-derivatized β1AR crystals, a cavity has been shown to be in contact with the cholesterol-binding pocket. Monitoring the binding of a cholesterol analogue in solution has explained the function of cholesterol as a negative allosteric modulator of β1AR.

    • Layara Akemi Abiko
    • , Raphael Dias Teixeira
    •  & Stephan Grzesiek

  • News & Views |

    Malleicyprols are highly reactive polyketides responsible for virulence in some pathogenic bacteria. Now, the enzyme that constructs the cyclopropanol warhead of malleicyprols has been identified. This enzyme could represent a useful target for developing new antivirulence therapeutics.

    • Elijah Abraham
    •  & Rebecca A. Butcher

  • Article
    | Open Access

    Burkholderia pseudomallei is a species of bacteria that poses a global health threat and, more generally, bacteria of the Burkholderia pseudomallei group cause severe diseases that are recalcitrant to treatment with antibiotics. Now, it has been shown how these infamous pathogens repurpose the widespread enzyme BurG to produce a reactive cyclopropanol head group found in the virulence-promoting malleicyprol toxins. Interrupting the synthesis of the cyclopropanol warhead is a potential route for developing antivirulence treatments.

    • Felix Trottmann
    • , Keishi Ishida
    •  & Christian Hertweck

  • Article |

    The introduction of fluorine into a drug molecule can alter the biological responses to it, including modulating bioavailability, pharmacokinetics and selectivity. Now, a hybrid polyketide/fatty acid synthase multienzyme has been designed to incorporate fluorinated precursors during polyketide biosynthesis in an approach that provides new chemoenzymatic access to fluorinated natural compounds.

    • Alexander Rittner
    • , Mirko Joppe
    •  & Martin Grininger

  • Perspective |

    Droplet interface bilayers (DIBs) are a type of artificial bilayer that can act as cell membrane mimics. This Perspective surveys how DIBs can be used to mimic key cellular features (such as bilayer asymmetry) and processes (such as drug movement), and discusses challenges that need to be overcome to enable DIBs to reach their full potential as biomimetic model membranes.

    • Elanna B. Stephenson
    • , Jaime L. Korner
    •  & Katherine S. Elvira

  • Article |

    A genetically encoded phototrigger based on a xanthone amino acid can expand the scope of time-resolved serial femtosecond crystallography beyond naturally photoactive proteins. This approach has been used to uncover metastable reaction intermediates that occur prior to C–H bond activation in a human liver fatty-acid-binding protein mutant.

    • Xiaohong Liu
    • , Pengcheng Liu
    •  & Jiangyun Wang

  • Article |

    Metal-free amyloid-β (Aβ) and metal-bound Aβ (metal–Aβ) are found in the brain of patients with Alzheimer’s disease. Now, it has been shown that the conformation of a native neuropeptide, somatostatin, is changed in the presence of copper ions, Aβ and metal–Aβ. The conformational change results in a loss of function of somatostatin as a neurotransmitter and a gain of function as a modulator against metal–Aβ.

    • Jiyeon Han
    • , Jiwon Yoon
    •  & Mi Hee Lim

  • Article |

    The composition of toxic protein aggregates associated with neurodegenerative diseases is difficult to determine. Now, a method has been developed that can capture amyloid-containing aggregates in human biofluids using a structure-specific chemical dimer. This method—known as amyloid precipitation—enables unbiased determination of the molecular composition and structural features of the in vivo aggregates.

    • M. Rodrigues
    • , P. Bhattacharjee
    •  & D. Klenerman

  • Article |

    Developing stimuli-responsive bioorthogonal tetrazine ligations remains highly challenging, but a versatile approach that uses photocaged dihydrotetrazines has now been developed. Photouncaging results in the spontaneous formation of reactive tetrazines that rapidly react with dienophiles such as trans-cyclooctenes. As a demonstration, the method was used for live-cell labelling with single-cell precision and light-triggered drug delivery.

    • Luping Liu
    • , Dongyang Zhang
    •  & Neal K. Devaraj

  • News & Views |

    Amino-containing four-carbon threose nucleic acids (TNAs) have long been considered to be prebiotically irrelevant due to their difficult formation. Now, a prebiotically plausible route to 3′-amino-TNA nucleoside triphosphate has been developed, raising the possibility of 3′-amino-TNA as a non-canonical nucleic acid during the origin of life.

    • Yingyu Liu
    •  & Yajun Wang

  • Article |

    Nucleotides are essential to the origins of life, and their synthesis is a key challenge for prebiotic chemistry. Contrary to prior expectation, non-canonical 3′-amino-TNA nucleosides are shown to be synthesized diastereoselectively and regiospecifically under prebiotically plausible conditions. The enhanced reactivity of 3′-amino-TNAs also promotes their selective non-enzymatic triphosphorylation in water.

    • Daniel Whitaker
    •  & Matthew W. Powner

  • Article |

    The biochemical roles and mechanisms of multiphase membraneless organelles are not yet well understood. Now, multiphase peptide droplets have been shown to sort RNA based on whether it is single- or double-stranded, as well as impact RNA duplexation through in-droplet thermodynamic equilibria. This work provides insight into possible primitive mechanisms for multicompartment intracellular condensates and can aid in the design of functional artificial membraneless organelles.

    • Saehyun Choi
    • , McCauley O. Meyer
    •  & Christine D. Keating

  • Article
    | Open Access

    A strategy for protecting redox-active ortho-quinones, which show promise as anticancer agents but suffer from redox-cycling behaviour and systemic toxicity, has been developed. The ortho-quinones are derivatized to redox-inactive para-aminobenzyl ketols. Upon amine deprotection, an acid-promoted, self-immolative C–C bond-cleaving 1,6-elimination releases the redox-active hydroquinone. The strategy also enables conjugation to a carrier for targeted delivery of ortho-quinone species.

    • Lavinia Dunsmore
    • , Claudio D. Navo
    •  & Gonçalo J. L. Bernardes

  • Article
    | Open Access

    Analogues of mRNA 5′ caps containing a photo-cleavable group have now been developed. These so-called FlashCaps can be used for routine in vitro transcription to make long mRNAs containing a cap. In cells, the capped mRNAs are translationally muted; however, upon irradiation by light, the photo-cleavable group is removed without leaving any remaining modification and mRNA is then translated into the corresponding protein.

    • Nils Klöcker
    • , Florian P. Weissenboeck
    •  & Andrea Rentmeister

  • Article |

    SynGAP and PSD-95 are two abundant proteins that form a complex and undergo liquid–liquid phase separation (LLPS) in the postsynaptic density of neurons. Now, O-GlcNAcylation of SynGAP has been found to suppress LLPS of the SynGAP/PSD-95 complex, and O-GlcNAc-dependent LLPS was also shown to be dynamically regulated by the enzymes O-GlcNAc transferase and O-GlcNAcase.

    • Pinou Lv
    • , Yifei Du
    •  & Xing Chen

  • Article
    | Open Access

    Phytochromes regulate plant growth by sensing far-red light through the photoisomerization of their protein-bound chromophores. In the phytochrome Agp2, it has now been demonstrated that ultrafast proton-transfer occurs from the chromophore to a protein–water network before photoisomerization, inducing protein changes on the ultrafast timescale. These protein changes develop further on longer timescales, resulting in an activated protein conformation.

    • Yang Yang
    • , Till Stensitzki
    •  & Karsten Heyne

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