Biochemistry articles within Nature Chemistry

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  • Perspective |

    Antibody–drug conjugates have shown considerable promise for treating disease. However, in order to deliver their full potential, sophisticated site-specific conjugation technologies are needed. This Perspective provides an overview of the different methods used for the site-specific attachment of cytotoxic agents to antibodies.

    • Vijay Chudasama
    • , Antoine Maruani
    •  & Stephen Caddick

  • Article |

    Intracellular bodies called liquid organelles are rich in nucleic acids and proteins, and are thought to occur by liquid–liquid phase coexistence. Now, enzymatic control over the phosphorylation state of a simple cationic peptide, thereby altering its electrostatic interaction with RNA, has been shown to drive formation and dissolution of droplets that mimic these intracellular liquid bodies.

    • William M. Aumiller Jr
    •  & Christine D. Keating

  • Article |

    Incorporation of a π-clamp—a four-residue sequence (Phe-Cys-Pro-Phe)—into a protein enables the site-specific modification of the π-clamp cysteine side-chain. The π-clamp can be genetically encoded and does not require protecting-groups or catalysts to provide selective conjugation.

    • Chi Zhang
    • , Matthew Welborn
    •  & Bradley L. Pentelute

  • Perspective |

    Synthetic vaccines offer one method to avoid the drawbacks associated with vaccines derived from whole organisms. This Perspective highlights the improvements and significant recent progress that has been achieved in developing well-defined synthetic vaccines using a variety of molecular antigens.

    • Lyn H. Jones

  • Article |

    Copper is a transition metal ion essential for the regulation of cellular oxidative stress and ATP production. Now, the inhibition of copper-trafficking proteins by a small molecule has been shown to significantly reduce proliferation of cancer cells. The results indicate that copper-trafficking proteins could represent new anti-tumour therapeutic targets.

    • Jing Wang
    • , Cheng Luo
    •  & Chuan He

  • Article |

    [Fe]-hydrogenase has an iron-guanylylpyridinol cofactor and catalyses the reversible hydrogenation of a methenyl-tetrahydromethanopterin. Now, [Fe]-hydrogenase has been reconstituted using synthetic cofactor mimics. The enzyme containing a mimic with a 2-hydroxy-pyridine group was active, whereas one containing a 2-methoxy-pyridine group was inactive. This result, together with DFT computations, supports a catalytic mechanism involving the deprotonated pyridinol hydroxy group as a proton acceptor.

    • Seigo Shima
    • , Dafa Chen
    •  & Xile Hu

  • News & Views |

    Synthetic oligomers could potentially expand beyond the functions offered by proteins and nucleic acids. However, this requires precise methods for controlling their folding and self-assembly. Now, it is shown that two drastically different supramolecular architectures can be fabricated from closely related sequences using a single biomimetic scaffold.

    • W. Seth Horne

  • Article |

    O-linked N-acetyl-glucosamine (O-GlcNAc) has been identified as an endogenous modification of α-synuclein; however, its effect on the properties of the protein is unclear. Now, recombinant protein and synthetic peptides have been combined to produce both unmodified and site-specifically O-GlcNAc-modified α-synuclein. The O-GlcNAc modification at threonine 72 was shown to inhibit the aggregation and associated toxicity of α-synuclein.

    • Nicholas P. Marotta
    • , Yu Hsuan Lin
    •  & Matthew R. Pratt

  • Article |

    Protein PEGylation is routinely used to produce molecules with improved pharmacokinetic properties. However, despite their importance, the structure of PEGylated proteins has remained elusive. Now, the first crystal structure of a model β-sheet protein modified with a single PEG chain has been reported. NMR spectroscopy data indicates that the protein and PEG behave as independent domains.

    • Giada Cattani
    • , Lutz Vogeley
    •  & Peter B. Crowley

  • Article |

    The question of how divalent metal ions direct the folding of ribozymes is a major unsolved problem. A computational model has now been used to reveal the molecular mechanism by which Mg2+ drives the Azoarcus ribozyme into a catalytically functional state. Simulations also show that although Ca2+ drives folding it leaves the active site unstable.

    • Natalia A. Denesyuk
    •  & D. Thirumalai

  • News & Views |

    Preparation and structural characterization of the catalytic intermediates of two similar thiolate-ligated haem proteins (cytochrome P450 Compound-I and chloroperoxidase Compound-I) has explained the structural basis for the difference in their reactivity.

    • Ilia G. Denisov
    •  & Stephen G. Sligar

  • Article |

    Cytochrome P450 (P450) and chloroperoxidase (CPO) are both thiolate-ligated haem proteins that form a ferryl radical species called compound I. P450-I is, however, significantly more reactive than CPO-I. Variable-temperature Mössbauer and X-ray absorption measurements have now shown that increased electron donation from the axial thiolate ligand in P450-I may explain its greater propensity for C–H bond activation.

    • Courtney M. Krest
    • , Alexey Silakov
    •  & Michael T. Green

  • Article |

    The reactivity of a monooxygenase (P450 PikC) has been modified through protein and substrate engineering, and applied to the oxidation of unactivated methylene C–H bonds. The protein engineering was guided by using molecular dynamics and quantum mechanical calculations to develop a predictive model for substrate scope, site selectivity and stereoselectivity of the C–H hydroxylation.

    • Alison R. H. Narayan
    • , Gonzalo Jiménez-Osés
    •  & David H. Sherman

  • Article |

    The use of kinetic simulations to guide the design of competitive hybridization probe systems is shown to enable high selectivity for single-nucleotide variants. Using this approach across 44 cancer mutation/wild-type sequence pairs showed between a 200- and 3,000-fold higher binding affinity than the corresponding wild-type sequence. In combination with PCR amplification this method enabled the detection of a 1% concentration of variant alleles in human genomic DNA.

    • Juexiao Sherry Wang
    •  & David Yu Zhang

  • Article |

    During the early stages of life on Earth sophisticated RNA catalysts must have formed from simple precursors. Here it is shown that freeze–thaw cycles can drive the assembly of complex RNA polymerase ribozymes from networks of short RNA oligonucleotides through an unanticipated RNA chaperone effect.

    • Hannes Mutschler
    • , Aniela Wochner
    •  & Philipp Holliger

  • News & Views |

    Symbiotic bacteria synthesize many specialized small molecules; however, establishing the role these chemicals play in human health and disease has been difficult. Now, the chemical structure and mechanism of the Escherichia coli product colibactin provides insight into the link between this secondary metabolite and colorectal cancer.

    • Eric W. Schmidt

  • Article |

    Structural elucidation of a peptide natural product has revealed an unprecedented post-translational modification involving formation of a carbon–carbon bond between the side-chains of lysine and tryptophan. This motif defines a new family of cyclic peptides. Biochemical studies reveal that this C-C bond is generated by a radical SAM enzyme, and delineate its catalytic mechanism.

    • Kelsey R. Schramma
    • , Leah B. Bushin
    •  & Mohammad R. Seyedsayamdost

  • Article |

    Photoswitching of phytochromes is based on the isomerization of the tetrapyrrole chromophore, and eventually leads to the (de)activation of an enzymatic output module. Now it has been shown that both the structural changes associated with photoswitching and the thermal decay of the light-activated state are coupled to proton translocations in the chromophore pocket.

    • Francisco Velazquez Escobar
    • , Patrick Piwowarski
    •  & Peter Hildebrandt

  • News & Views |

    Supramolecular assembly has been used to design and create new proteins capable of performing biomimetic functions in complex environments such as membranes and inside living cells.

    • Arnold J. Boersma
    •  & Gerard Roelfes

  • News & Views |

    A supramolecular polymer comprising stacked artificial chromophores to which zinc(II) complexes are appended is able to respond to enzymatic hydrolysis in aqueous solution. The assembly of molecules can twist reversibly and quickly in response to changes in the type of adenosine phosphate present.

    • David B. Amabilino

  • Article |

    The extraction of (bio)molecules from fluid mixtures is vital for applications ranging from biomedical diagnostics to environmental analysis. Now a robust chemomechanical sorting system for the extraction of thrombin is described in which pH-dependent binding of the analyte to a specific aptamer is combined with volume changes of the pH-responsive hydrogel in a biphasic microfluidic regime, resulting in a catch-and-release system.

    • Ankita Shastri
    • , Lynn M. McGregor
    •  & Ximin He

  • News & Views |

    In their natural environment, membrane proteins are surrounded by lipids, but the effect that the lipids have on the proteins is not easy to assess. Now, controlling the extent of delipidation has enabled the study of these interactions.

    • Sophie R. Harvey
    •  & Vicki H. Wysocki

  • Article |

    Charge transport in molecular systems is typically through coherent tunnelling over a short distance or incoherent hopping over a long distance. An intermediate regime between those two transport mechanisms has now been found for DNA systems with stacked guanine–cytosine sequences.

    • Limin Xiang
    • , Julio L. Palma
    •  & Nongjian Tao

  • Article |

    Defining the lipid composition that exists around a membrane protein complex in natural bilayers is a challenging task. Now, key lipids that are important for the structure and function of an ABC transporter have been revealed by systematically removing layers of lipids, and using mass spectrometry to monitor those that remained closely associated with the membrane protein.

    • Chérine Bechara
    • , Anne Nöll
    •  & Carol V. Robinson

  • Research Highlights |

    • Leonie Mueck

  • News & Views |

    A combined experimental and theoretical study of the biosynthesis of a family of antibacterial natural products has uncovered some of the finer details of unusual stereoselectivity observed in a peptide cyclization.

    • Bryan Jones
    •  & Romas J. Kazlauskas

  • Article |

    The stereochemical outcome of enzyme-catalysed reactions with physiological substrates is typically governed by the well-defined geometry of the enzyme active site. Now, a rare example is reported where the substrate controls the stereoselectivity of a Michael-type addition during lanthipeptide biosynthesis.

    • Weixin Tang
    • , Gonzalo Jiménez-Osés
    •  & Wilfred A. van der Donk

  • News & Views |

    Enhancing the structural diversity of peptide natural products relies on synthetic modifications that are typically not chemo- or regioselective. A nonribosomal peptide synthetase has now been engineered to incorporate a non-natural amino acid containing a reactive bio-orthogonal handle.

    • Jaclyn M. Winter
    •  & Yi Tang

  • News & Views |

    Oxidation of 5-methylcytosine has been proposed to mediate active and passive DNA demethylation. Tracking the history of DNA modifications has now provided the first solid evidence that 5-hydroxymethylcytosine is a stable epigenetic modification.

    • Pijus Brazauskas
    •  & Skirmantas Kriaucionis

  • Article |

    The adenine analogue 2-aminopurine has been considered as intrinsically fluorescent and is widely used in biochemical assays to probe DNA and RNA structure. It is now shown that the molecule alone is nearly non-fluorescent, however, its fluorescence is increased by up to 95 times through hydrogen bonding to a single water molecule.

    • Simon Lobsiger
    • , Susan Blaser
    •  & Samuel Leutwyler

  • Article |

    Recognition, differentiation and sensing of small molecules displaying only sparse functionalities using artificial receptors is extremely challenging. Now a method to selectively bind and recognise low-epitope targets has been developed. The approach uses the formation of ternary complexes between small-molecule targets, their non-specific organic (or organometallic) receptors, and aptamers.

    • Kyung-Ae Yang
    • , Mihaela Barbu
    •  & Milan N. Stojanovic

  • Research Highlights |

    • Claire Hansell

  • News & Views |

    Bicyclic peptides that are cell-permeable and can inhibit an intracellular target have been developed. These peptides consist of two rings: one enables the peptide to pass through the membrane, the other can inhibit the target.

    • Rob M. J. Liskamp

  • Article |

    Non-haem iron(III)-peroxo complexes that bind redox-inactive metal ions are synthesized to investigate the role of the Ca2+ ion in the oxidation of water to dioxygen in photosystem II. The electrochemical properties and reactions of these compounds with an electron donor and an acceptor are found to be markedly dependent on the Lewis acidity of redox-inactive metal ions.

    • Suhee Bang
    • , Yong-Min Lee
    •  & Wonwoo Nam

  • Article |

    Disulfide bonds formed between two cysteine residues are important in the folding and stability of proteins. Now, unnatural amino acids with side-chains that contain two thiol groups are described. Incorporation of these dithiol amino acids into a serine protease inhibitor and a nicotinic acetyl choline receptor antagonist is shown to increase their inhibitory activity.

    • Shiyu Chen
    • , Ranganath Gopalakrishnan
    •  & Christian Heinis

  • Books & Arts |

    • Timothy W. Lyons

  • Article |

    Amiloride is a widely used diuretic that blocks epithelial sodium channels (ENaCs); however, the functional role of the different ENaC isoforms is still poorly understood and no pharmacological tools exist to differentiate between them. Now, photoswitchable amilorides that enable the optical control of ENaCs, and can distinguish between different ENaC isoforms have been developed.

    • Matthias Schönberger
    • , Mike Althaus
    •  & Dirk Trauner

  • News & Views |

    Protein-based protonic conductivity plays an important role in nature, but has been explored little outside of a biological setting. Now, proton conductors have been developed based on the squid protein reflectin, and integrated with devices for potential bioelectronic applications.

    • Marco Rolandi

  • Article |

    Proton-conducting materials have proved useful for renewable energy applications and bioelectronics technologies. The proton conductivity of thin films made from reflectin — a cephalopod structural protein — is now reported. Reflectin's electrical properties compare favourably to those of artificial materials, and have enabled the demonstration of protein-based protonic transistors.

    • David D. Ordinario
    • , Long Phan
    •  & Alon A. Gorodetsky

  • News & Views |

    The lomaiviticins are exceedingly potent antibiotic agents, but the mechanism responsible for this activity has so far been unclear. Now, efficient generation of double-strand breaks in DNA by lomaiviticin A has been linked to the remarkable cytotoxicity of these diazobenzofluorene-containg natural products.

    • Kent S. Gates

  • Article |

    Magnetic resonance imaging of gene expression has been limited by the low molecular sensitivity of conventional 1H-MRI. To overcome this limitation, the first genetically encoded reporters for hyperpolarized xenon MRI have been developed. These expressible reporters, based on gas-filled protein nanostructures from buoyant microorganisms, are detectable at picomolar concentrations.

    • Mikhail G. Shapiro
    • , R. Matthew Ramirez
    •  & Vikram S. Bajaj

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