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This Collection highlights a selection of recent studies published in Communications Chemistry relating to the structure, function, modification and detection of biomolecules. The biocatalysis and biosynthesis section features articles that probe mechanisms of enzyme activity, unearth new enzymes from biosynthesis studies, and explore applications in chemical synthesis. The structural biology section showcases new insights into the structure and function of biomolecules from modern analytical and computational chemistry. The chemical probes section features articles that showcase chemical tools for the study of biological function, including probe development, labeling methods and bioimaging. Finally, the medicinal chemistry section highlights advances into target identification and the design and synthesis of new lead compounds.
The cluster approach is a very valuable technique for elucidating reaction mechanisms of enzymes. Here, the authors discuss the current status of this methodology, highlighting its strengths and weaknesses, and argue that it should be the method of choice for investigating enzymatic reaction mechanisms.
In light of bacterial resistance to β-lactam antibiotic drugs, understanding the hydrolysis reaction of β-lactamases is crucial. Here the authors use machine learning based regression algorithms to analyze the catalytic energy landscape of TEM-1.
L-amino acid oxidases can convert racemic amino acids to D-isomers, but stable and structure-determined oxidases are scarce. Here, the authors report the structures, stabilities, and activities of two ancestral L-amino acid oxidases.
Threonine is a biosynthetic precursor to dimethylpyrazine derivatives, but the pathway by which this occurs is not fully established. Here l-throenine-3-dehydrogenase and 2-amino-3-ketobutyrate CoA ligase together are shown to convert l-threonine to dimethylpyrazine derivatives as a byproduct of glycine metabolism.
Diels-Alderases remain rare in nature, particularly those catalysing intermolecular reactions. Here two natural Diels-Alderases are shown to catalyse exo-selective intermolecular Diels-Alder reactions on non-natural substrates.
Pimaranes are diterpenoid natural products with poorly characterised biosynthetic pathways. Here pimaranetype diterpenoid synthases are functionally and structurally characterised and shown to exploit distinct modes of intermediate stabilisation.
Camptothecin derivatives are precursors of potent anticancer agents, but their biosynthesis remains largely unknown. Here two cytochrome P450 monooxygenases are shown to regiospecifically oxidize camptothecin, yielding 10- and 11- hydroxylated derivatives, which are subsequently used to produce a suite of known anticancer drugs and derivatives.
Multidimensional NMR spectroscopy can provide insight into the unfolding of proteins in cells, but may be sensitive to the choice of residue used as a reference. Here 2D 1H-15N NMR is used to obtain thermodynamic parameters of unfolding of Yfh1, relying on an internal standard to normalise peak volumes.
Near-infrared fluorescent proteins engineered from bacterial phytochromes are important for deep-tissue imaging in vivo, but the mechanism through which they bind to chromophores is not fully understood. Here the authors structurally analyze biliverdin binding to miRFP proteins using time-resolved stimulated Raman spectroscopy and quantum mechanical/molecular mechanics calculations.
Dioxygen protein sensors undergo structural distortions upon binding, but the role of heme distortion in allostery is unclear. Here heme distortion in a bacterial dioxygen sensor is studied using picosecond time-resolved electronic absorption spectroscopy and shown to control the allosteric equilibrium.
Hirudin is a widely studied model for folding of disulfide-rich proteins, which folds through a slow pathway with highly heterogeneous intermediates and scrambled isomers before it reaches its native state. Here the effect of native and non-native diselenide bridges on the kinetics, yield, and heterogeneity of hirudin folding are systematically explored.
Nidovirus RNA synthesis machineries catalyze nucleotide transfer, but characterization of this activity is limited using existing methods. Here the nucleotidyl transferase activity of SARSCoV-2 replicase proteins is characterized by mass spectrometry of GMP and UMP protein adducts, allowing identification of nucleotidylation sites in vitro.
Solution NMR provides an information-rich technique to monitor the unfolding process and probe the heterogeneity of protein unfolding. Differences in unfolding dynamics of core and peripheral residues during the cold denaturation of Yfh1 are followed in the present study by 1H-15N HSQC spectroscopy.
Cryptochromes are photoreceptors involved in biological magnetoreception, but the interplay of conformation, electronic coupling, and molecular motion remains poorly understood. Here, time-resolved electron paramagnetic resonance experiments support a role for hydration dynamics control electronic coupling in a cryptochrome.
Dissolution dynamic nuclear polarisation allows for dramatic signal enhancement in protein NMR spectroscopy, but loss of polarisation limits temporal and structural resolution. Here polarisation of the solvent and subsequent transfer to the target molecule enables selective detection of hyperpolarised residues.
Force-dependent transitions can provide insights into the free-energy landscape of proteins. Here, the authors observe the folding and unfolding dynamics of the model protein Csp using magnetic tweezers, from which a free-energy landscape with two energy barriers and a transient intermediate state is constructed.
Calculating the thermodynamic properties of biochemical systems typically requires resource intensive, multi-step molecular simulations. Here, two deep neural network machine learning methods generate the thermodynamic state of dynamic water molecules in a protein environment solely from information on the static protein structure.
Enzymes may behave differently at high pressures found in environments such as the ocean floor, but molecular dynamics force fields are not well characterized at high pressures. Here the CHARMM36m force field is validated against NMR data at variable pressures up to 2500 bar, using ubiquitin as a model protein.
Water ligands found in the oxygen-evolving Mn4CaO5 cluster in photosystem II are thought to be important during photosynthesis, but the nature of the proton-releasing substrate water molecules is disputed. Here the pKa values of four key water molecules are estimated, with implications for the mechanism of water oxidation.
How phosphorylation regulates the binding of the intrinsically disordered protein kinase inducible domain to KIX is unclear. Here bias-exchanged metadynamics simulations of the macromolecular complex suggest that hydrophobic interactions in the phosphorylated domain create a hydrophobic residue cluster which is selective for KIX binding.
Polyethylene glycol (PEG) is a widely used, biocompatible material, but can promote the development of anti-PEG antibodies. Here, crystal structures of an anti-PEG antibody binding fragment bound to PEG are reported and key binding residues are identified by site-directed mutagenesis.
Understanding the downstream signal transduction process of the CXCL12–CXCR4–Gαi tricomplex could prove useful in the development of anticancer and antimetastatic drugs. Here the authors propose an internal water channel formation model for CXCL12-bound CXCR4 in complex with Gαi-protein upon activation for downstream signaling.
Nucleic acid probes that bind to cancer-related genes have potential as diagnostic tools. Here parameters governing the binding of locked nucleic acid probes to three oncogenes, including effects of molecular crowding and polyelectrolytes, are characterized and used to inform the design of a bead-bait RNA genotyping assay.
Serinol nucleic acid and L-threoninol nucleic acid can bind to RNA and DNA, endowing them with potential as nucleic acid-based drugs. Here the authors prepare single crystals of L-aTNA/RNA and SNA/RNA heteroduplexes to further our structural understanding of how synthetic nucleic acids hybridize with natural nucleic acids.
Photochemical and electrochemical approaches to protein and peptide modification offer a valuable complement to the use of stoichiometric reagents. Here recent developments in bioconjugation methodology relying on single electron transfer are described.
Near-infrared fluorescence probes that respond to pH are effective tools to analyse pH-driven biological processes but share common limitations. Here the authors report a germanium-rhodamine based near-infrared probe with appropriate pKa value for biological applications and improved photostabillity and quantum yield.
Lysine trimethylation is a key post-translational modification, which some epigenetic reader proteins detect through binding to aromatic cages involving cation-π interactions. Here systematic modification of the aromatic cage reveals that weaker cation-π interactions do not correlate with weaker binding owing to a compensating release of bound water molecules.
Rhodamine derivatives are useful spirocyclic fluorescent probes, but tuning their properties can involve laborious synthesis and screening. Here quantum chemical modeling of the equilibrium between open and closed forms allows prediction of the pK of cyclisation and rational tailoring of properties of interest.
The folding and conformational dynamics of proteins can be studied using optical tweezers with the aid of DNA handles. Here this assay is extended to simultaneously visualize the binding of complexing partners while monitoring the induced conformational changes on the protein.
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.
Proximity-based ligations commonly require an external stimulus such as a catalyst or irradiation, or highly reactive functional groups. Here the reaction of alpha effect nucleophiles and 2,5-dioxopentanyl derivatives allows direct proximity-based ligation while avoiding highly reactive moieties.
Dynamic nuclear polarization coupled with 15N magnetic resonance imaging can afford quantitative imaging of biologically important metal ions. Here the authors prepare 15N-enriched, d6-deuterated tris(2-pyridylmethyl)amine as an MRI sensor for freely available Zn2+.
Magnetic resonance imaging of hyperpolarized contrast agents has enabled unprecedented imaging capabilities in a biomedical setting, but its widespread application is hindered by the time and costs associated with preparing hyperpolarized carbon-13 samples. Here, the authors demonstrate virtually-continuous production of batches of highly-hyperpolarized carbon-13 contrast agents every 15 s within an MRI system without a stand-alone polarizer.
For many applications, positron emission tomography tracers must be produced with high specific activity. Here the authors identify variables leading to increased specific activity when tracers are synthesized in microliter volumes, and show that specific activity can influence tracer biodistribution.
Promising treatments for neurogenerative disorders may involve targeting kinetic intermediates, including α-synuclein oligomers. Here a kinetic method for quantifying oligomer populations is used to screen small molecule inhibitors of oligomerisation and gain mechanistic insight into their modes of action.
Angiotensin converting enzyme 2 (ACE2) has been identified as a cardiovascular disease biomarker and the primary receptor utilized by SARS-CoV-2, but developing serum-stable, selective and high-affinity binders for this target is challenging. Here, the authors use affinity selection-mass spectrometry to identify multiple high affinity ACE2-binding peptides from canonical and noncanonical peptidomimetic libraries containing 200 million members.
Carbohydrate–protein interactions are key for cell–cell and host–pathogen recognition, but their hydrophilic nature makes the development of drug-like inhibitors a challenge. Here, screening of fragment libraries identifies metal-binding pharmacophores as novel scaffolds for the inhibition of Ca2+-dependent carbohydrate–protein interactions.
Fibroblast growth factor receptor 4 (FGFR4) is a promising target for the treatment of hepatocellular carcinoma, but current FGFR4 covalent inhibitors target only one of the two cysteine residues (Cys477 or Cys552) that provide FGFR4-specificity. Here, a dual-warhead covalent FGFR4 inhibitor that can covalently target both cysteine residues of FGFR4 is reported, and strong selectivity for FGFR4 is observed.
Platinum(IV) complexes have the potential to overcome several limitations and reduce adverse effects of platinum-based cancer therapy. Resistance to clinically approved platinum(II) drugs is, at least in part, associated with elevated levels of glutathione. Here, the authors report on an oxaliplatin-based platinum(IV) prodrug, which releases L-buthionine-S,R-sulfoximine, an inhibitor of the rate-limiting enzyme in glutathione biosynthesis, to circumvent glutathione-based resistance mechanisms.
Mutations to oncogenic protein KRAS are responsible for some of the deadliest cancers, and KRAS is thus a key target for new antitumour agents. Here, a short bis-histidine peptide derived from the αH helix of the cofactor SOS1 is designed and shown to reversibly bind to KRAS with high affinity upon coordination to Pd(II), inhibiting KRAS-activated pathways in live cells.
Fidaxomicin is a narrow spectrum antibiotic, and broadening its activity through structural modification could provide new antibiotics. Here semi-synthetic derivatives are prepared through site-selective esterification and allylic substitution to efficiently modify or substitute key carbohydrate moieties.
The L-lactate-specific transporter SfMCT is a model SLC16 family homologue for the determination of inhibitors and potential drugs. Here, starting from a weakly-binding non-transported ligand, nanomolar affinity inhibitors of SfMCT are developed and crystal structures of the transporter-ligand complexes are presented unveiling interactions at the atomic level.
Benzoazepine is a well-known pharmacophore presented in several marketed drugs. Here, the authors report the isolation and total syntheses of asperazepanones A and B from coral-derived Aspergillus candidus, two novel pyrrolinone-fused benzoazepine alkaloids with potent anti-inflammatory activities.
Non-alcoholic steatohepatitis demands multiple modes of action for robust therapeutic efficacy. Here the authors design and optimize a triple modulator of farnesoid X receptor and peroxisome proliferator-activated receptors α and δ that counteracts hepatic inflammation and reverses hepatic fibrosis in mice.
Protein-ligand binding can induce the formation of cryptic allosteric pockets not found in the unbound protein, but predicting this computationally can be challenging. Here a combined computational and experimental workflow identifies ligands for H. pyloriglutamate racemase, finding that coupled dynamics of the enzyme dimer are dampened by ligand binding.
The human fibroblast growth factor receptors (FGFRs) are attractive targets for cancer therapy, but the structural basis for kinase targeting and gatekeeper mutations of covalent FGFR inhibitors are not fully understood. Here the authors report and discuss the potency and selectivity of FGFR inhibitors FIIN-2, TAS-120 and PRN1371 based on the co-crystal structures of SRC/FIIN-2, SRC/TAS-120 and FGFR4/PRN1371 complexes.
Understanding the molecular interactions between proton-dependent oligopeptide transporters and their inhibitors is key to drug and tool development, but high-resolution co-crystal structure data remains scarce. Here, the authors report the crystal structure of YePEPT-K314A in complex with the potent inhibitor Lys[Z(NO2)]-Val, revealing the molecular interactions involved in inhibitor binding and a previously undescribed hydrophobic pocket.