Molecular biology articles within Nature Chemistry

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  • News & Views |

    Genetic code expansion beyond α-amino acids is a major challenge, in which stitching together non-natural building blocks within the ribosome is a critical barrier. Now, the molecular determinants for the efficient incorporation of non-natural amino acids into the ribosome have been unlocked, accelerating ribosomal synthesis.

    • Souvik Sinha
    • , Mohd Ahsan
    •  & Giulia Palermo

  • Research Briefing |

    Protein translation is the ultimate paradigm for sequence-defined polymer synthesis. To introduce non-canonical monomers into the genetic code of living organisms, pairs of biomolecules known as aminoacyl-tRNA synthetases (aaRSs) and transfer RNAs (tRNAs) are required. The discovery and engineering of five such pairs, that do not interfere with each other or the aaRS–tRNA pairs of a bacterial host, sets the stage for highly modified genetically encoded biopolymers.

  • 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 |

    Synthesis of peptidyl-tRNAs is challenging because there are no enzymes that can directly attach the desired peptide to tRNA. Now it has been shown that a chemoenzymatic approach based on native chemical ligation can be used for the semi-synthesis of peptidyl-tRNAs for structural/biochemical studies of arrested and non-arrested ribosome complexes.

    • Egor A. Syroegin
    • , Elena V. Aleksandrova
    •  & Yury S. Polikanov

  • 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 |

    Histone H1 binds to nucleosomes with ultrahigh affinity, implying residence times incompatible with efficient biological regulation. Now it has been shown that the disordered regions of H1 retain their large-amplitude dynamics on the nucleosome, which enables a charged disordered histone chaperone to invade the H1–nucleosome complex and vastly accelerate H1 dissociation.

    • Pétur O. Heidarsson
    • , Davide Mercadante
    •  & Benjamin Schuler

  • Article
    | Open Access

    During polypeptide biosynthesis, a strong interaction can occur between a segment of an emerged, disordered nascent protein and the ribosomal surface. Now, it has been shown that competition between this ribosomal binding and the folding energetics of an immunoglobulin-like domain modulates the mechanism of co-translational folding.

    • Anaïs M. E. Cassaignau
    • , Tomasz Włodarski
    •  & John Christodoulou

  • Article |

    Non-canonical amino acids can be incorporated into proteins through translation of orthogonal mRNAs. Now, automating the design of orthogonal mRNAs—which are more selectively and efficiently translated—in combination with compact orthogonal aminoacyl-tRNA synthetase/tRNA expression systems, enables the incorporation of four distinct non-canonical monomers via a 68-codon genetic code.

    • Daniel L. Dunkelmann
    • , Sebastian B. Oehm
    •  & Jason W. Chin

  • 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 |

    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 |

    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 |

    I-motif DNA structures are thought to form in cytosine-rich regions of the genome and to have regulatory functions; however, in vivo evidence for the existence of such structures has so far remained elusive. Now an engineered antibody that is selective for i-motif structures has been developed and used to detect i-motifs in the nuclei of human cells.

    • Mahdi Zeraati
    • , David B. Langley
    •  & Daniel Christ

  • Article |

    An integrated native mass spectrometry and top-down proteomics method using Fourier transform ion cyclotron resonance has been developed for the characterization of macromolecular protein complexes. This approach directly yields primary to quaternary structural information in a single native top-down experiment.

    • Huilin Li
    • , Hong Hanh Nguyen
    •  & Joseph A. Loo

  • Article |

    Delayed resolution of G-quadruplexes during replication can induce localized loss of epigenetic information and changes in gene expression. Now, this effect has been used to discover biologically potent G-quadruplex ligands and to demonstrate that G-quadruplex stabilization can induce epigenetic changes that are heritable across cell divisions even after the ligand is removed.

    • Guillaume Guilbaud
    • , Pierre Murat
    •  & Shankar Balasubramanian

  • Article |

    Lysine-rich peptides from the ribosomal core and derived homolysine decapeptides of either L-, D- or mixed chirality have now been shown to enhance RNA polymerase ribozyme activity at low magnesium concentrations, accelerate ribozyme evolution and enable templated RNA synthesis within membranous protocells.

    • Shunsuke Tagami
    • , James Attwater
    •  & Philipp Holliger

  • Article |

    Non-coding RNAs are ubiquitous biomolecules with intricate three-dimensional folds that are difficult to characterize. This Article presents an information-rich strategy for inferring RNA structure by combining nucleotide-by-nucleotide mutagenesis with single-nucleotide-resolution chemical mapping.

    • Wipapat Kladwang
    • , Christopher C. VanLang
    •  & Rhiju Das

  • Article |

    Whereas synthetic DNA nanostructures are widely studied, the use of RNA as a structural building block is much less common. Now, it has been shown that tRNA molecules can be designed to assemble into a rigid and thermally stable square antiprism structure that may prove useful for delivery applications inside cells.

    • Isil Severcan
    • , Cody Geary
    •  & Luc Jaeger

  • Article |

    The time taken for a reactant to reach a target is best represented theoretically by a distribution of times. This distribution has now been calculated analytically and shows quantitatively that in the case of uncrowded environments, a reactant's starting point — in relation to the target — does not influence the search time. It does, however, have an effect in the case of crowded systems — leading to ‘geometry-controlled kinetics’.

    • O. Bénichou
    • , C. Chevalier
    •  & R. Voituriez

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