Hypoxia-inducible factor (FIH) is an oxygenase which post-translationally hydroxylates proteins and is implicated in a range of biological processes. Here a wide substrate tolerance for FIH is demonstrated, including for d-amino acids, where double hydroxylation of d-leucine is observed.
Structural and chemical biology
This collection highlights a selection of recent studies published in Communications Chemistry relating to the structure, function, and chemical modification of biomolecules. The Biocatalysis section features articles which probe mechanisms of enzyme activity, or engineer enzymes for new synthetic applications. The Computational Structural Biology section encompasses new insights into the structure and function of enzymes from modern computational chemistry. And under Bioconjugation we showcase tools for the study of biological function, including bioorthogonal labeling methods and environmentally responsive fluorescent probes.
These articles have been collated by Prof. Akane Kawamura, Editorial Board Member for Communications Chemistry, and Dr Andrew Bissette, Senior Editor.
Lysine methyltransferases (KMTs) play important roles in epigenetics. Here human KMTs are shown through a combination of experimental and computational methods to methylate non-natural histone peptides containing various non-lysine nucleophiles.
The merger of chemical and biocatalysis can offer powerful new options to synthetic chemists. Here a combination of a nickel-catalyzed Suzuki-Miyaura reaction and an enzymatic stereoselective reduction provides enantiomerically-enriched alcohols from amides in a single reaction vessel, in water.
The efficient biocatalytic processing of cellulose is a longstanding goal. Here, an ancient endogluconase is recreated using ancestral sequence reconstruction and the basis for its thermal stability and favourable catalytic properties are probed computationally.
Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases
Beta-lactams are important antiobiotics but synthesising functionalised derivatives in high enantiomeric purity can be challenging. Here malonyl-CoA derivatives are applied in an enantioselective multi-enzyme cascade, yielding beta-lactams bearing three contiguous chiral centres in high diastereomeric purity.
Biocatalytic methylation and demethylation via a shuttle catalysis concept involving corrinoid proteins
Regioselective methods for the reversible formation and breakage of C-O-ether bonds under mild conditions are desired. Here, the authors present a biocatalytic shuttle concept using corrinoid-dependent methyl transferases for demethylating various phenyl methyl ethers and functionalizing substituted catechols.
Glycerol is an abundant byproduct of the biofuel industry which holds promise as a platform chemical. Here glycerol is converted to value-added chemicals of varying degrees of reduction using thermostable multi-enzyme cascades.
Computational structural biology
An investigation of structural stability in protein-ligand complexes reveals the balance between order and disorder
The relationship between structural stability and ligand binding in proteins is debated. Here the structural robustness of a set of protein-ligand complexes is related to individual hydrogen bonds by dynamic undocking.
Allosteric effects in cyclophilin mutants may be explained by changes in nano-microsecond time scale motions
The relationship between molecular motion and catalysis in enzymes is debated. Here, simulations of cyclophilin A and three catalytically-impaired mutants reveal a nanosecond-scale interconversion between active and inactive conformations, orders of magnitude faster than previously suggested.
Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo
Displacement of water molecules from proteins can lead to higher affinity or selectivity of ligands, but measuring individual water binding energies is challenging. Here calculated binding free energies are used to estimate the stability of conserved water in 35 bromodomains and to predict the ease of displacement.
Proteins can undergo both heat and cold denaturation, and in marginally stable proteins this is often controlled by electrostatic frustration. Here, the authors find that residues essential for protein function are also structural determinants for cold denaturation.
Direct ring-strain loading for visible-light accelerated bioorthogonal ligation via diarylsydnone-dibenzo[b,f ][1,4,5]thiadiazepine photo-click reactions
Strained alkenes are valuable reagents for rapid and selective labeling of biomolecules but may undergo side-reactions. Here direct excitation of an azobenzene generates a strained nitrogen-nitrogen double bond in situ which reacts with a photochemically-generated nitrile imine, allowing the labeling of live cells with spatiotemporal control.
Development of a 1,3a,6a-triazapentalene derivative as a compact and thiol-specific fluorescent labeling reagent
Fluorescent probes are essential tools in chemical biology but their size may perturb systems under investigation. Here a small triazapentalene fluorophore is shown to selectively label thiols without influencing properties such as binding potency.
Ligand-directed protein labeling allows selective modification of native proteins but typically requires stoichiometric quantities of the labeling agent. Here a substoichiometric quantity of a peptide probe bound to a photocatalyst allows selective labeling of a target protein Cys residue in the presence of structurally similar proteins.
Chemoselective and photocleavable cysteine modification of peptides and proteins using isoxazoliniums
Selective labeling of biomolecules is a powerful technology for chemical biology. Here a silver-catalysed chemoselective modification of cysteine residues by isoxazolinium reagents is described.
Positive functional synergy of structurally integrated artificial protein dimers assembled by Click chemistry
Oligomerisation is widely used to engineer proteins and peptides with desirable properties. Here, covalent homodimers and heterodimers of fluorescent proteins are designed in silico and experimentally shown to exhibit differing spectral properties depending upon the structure of the protein-protein interface.
Catalytic N-modification of α-amino acids and small peptides with phenol under bio-compatible conditions
Phenol and cyclohexenone can interconvert by controlled palladium-catalyzed hydrogenation or oxidation, allowing N-functionalization of amines. Here this is applied to amino acids and small peptides, allowing a range of challenging substrates to be N-arylated using cyclohexenone or N-alkylated using phenol.