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Faraday Discussions May 2022The nonheme iron(IV)-oxido complex -N3-[(L)FeO(Cl)], where L is a derivative of the tetradentate bispidine 2,4-di(pyridine-2-yl)-3,7-diazabicyclo[3.3.1]nonane-1-one,...
The nonheme iron(IV)-oxido complex -N3-[(L)FeO(Cl)], where L is a derivative of the tetradentate bispidine 2,4-di(pyridine-2-yl)-3,7-diazabicyclo[3.3.1]nonane-1-one, has an = 1 electronic ground state and is the most reactive nonheme iron model system known so far, of a similar order of reactivity as nonheme iron enzymes (C-H abstraction of cyclohexane, -90 °C (propionitrile), = 3.5 s). The reaction with cyclohexane selectively leads to chlorocyclohexane, but "cage escape" at the [(L)Fe(OH)(Cl)]/cyclohexyl radical intermediate lowers the productivity. Ligand field theory is used herein to analyze the d-d transitions of [(L)FeO(X)] (X = Cl, Br, MeCN) in comparison with the thoroughly characterized ferryl complex of tetramethylcyclam (TMC = L; [(L)FeO(MeCN)]). The ligand field parameters and d-d transition energies are shown to provide important information on the triplet-quintet gap and its correlation with oxidation reactivity.
Topics: Cyclohexanes; Ferric Compounds; Iron; Ligands
PubMed: 35156976
DOI: 10.1039/d1fd00073j -
International Journal of Molecular... Aug 2022The equilibrium distribution of small molecules (ligands) between binding agents in heterogeneous media is an important property that determines their activity.... (Review)
Review
The equilibrium distribution of small molecules (ligands) between binding agents in heterogeneous media is an important property that determines their activity. Heterogeneous systems containing proteins and lipid membranes are particularly relevant due to their prevalence in biological systems, and their importance to ligand distribution, which, in turn, is crucial to ligand's availability and biological activity. In this work, we review several approaches and formalisms for the analysis of the equilibrium distribution of ligands in the presence of proteins, lipid membranes, or both. Special attention is given to common pitfalls in the analysis, with the establishment of the validity limits for the distinct approaches. Due to its widespread use, special attention is given to the characterization of ligand binding through the analysis of Stern-Volmer plots of protein fluorescence quenching. Systems of increasing complexity are considered, from proteins with single to multiple binding sites, from ligands interacting with proteins only to biomembranes containing lipid bilayers and membrane proteins. A new formalism is proposed, in which ligand binding is treated as a partition process, while considering the saturation of protein binding sites. This formalism is particularly useful for the characterization of interaction with membrane proteins.
Topics: Binding Sites; Ligands; Lipid Bilayers; Membrane Proteins; Protein Binding
PubMed: 36077155
DOI: 10.3390/ijms23179757 -
Biomolecules Nov 2022Allostery is a property of biological macromolecules featuring cooperative ligand binding and regulation of ligand affinity by effectors. The definition was introduced...
Allostery is a property of biological macromolecules featuring cooperative ligand binding and regulation of ligand affinity by effectors. The definition was introduced by Monod and Jacob in 1963, and formally developed as the "concerted model" by Monod, Wyman, and Changeux in 1965. Since its inception, this model of cooperativity was seen as distinct from and not reducible to the "sequential model" originally formulated by Pauling in 1935, which was developed further by Koshland, Nemethy, and Filmer in 1966. However, it is difficult to decide which model is more appropriate from equilibrium or kinetics measurements alone. In this paper, we examine several cooperative proteins whose functional behavior, whether sequential or concerted, is established, and offer a combined approach based on functional and structural analysis. We find that isologous, mostly helical interfaces are common in cooperative proteins regardless of their mechanism. On the other hand, the relative contribution of tertiary and quaternary structural changes, as well as the asymmetry in the liganded state, may help distinguish between the two mechanisms.
Topics: Ligands; Allosteric Regulation; Kinetics; Proteins
PubMed: 36359000
DOI: 10.3390/biom12111651 -
Critical Reviews in Biotechnology Dec 2020Tools for tuning transcription in mammalian cells have broad applications, from basic biological discovery to human gene therapy. While precise control over target gene... (Review)
Review
Tools for tuning transcription in mammalian cells have broad applications, from basic biological discovery to human gene therapy. While precise control over target gene transcription dosing with small molecules (drugs) is highly sought, the design of such inducible systems that meets required performance metrics poses a great challenge in mammalian cell synthetic biology. Important characteristics include tight and tunable gene expression with a low background, minimal drug toxicity, and orthogonality. Here, we review small-molecule-inducible transcriptional control devices that have demonstrated success in mammalian cells and mouse models. Most of these systems employ natural or designed ligand-binding protein domains to directly or indirectly communicate with transcription machinery at a target sequence, carefully constructed fusions. Example fusions include those to transcription activator-like effectors (TALEs), DNA-targeting proteins (e.g. dCas systems) fused to transactivating domains, and recombinases. Similar to the architecture of Type I nuclear receptors, many of the systems are designed such that the transcriptional controller is excluded from the nucleus in the absence of an inducer. Techniques that use ligand-induced proteolysis and antibody-based chemically induced dimerizers are also described. Collectively, these transcriptional control devices take advantage of a variety of recently developed molecular biology tools and cell biology insights and represent both proof of concept (e.g. targeting reporter gene expression) and disease-targeting studies.
Topics: Animals; Gene Expression; Gene Expression Regulation; Ligands; Mice
PubMed: 32862714
DOI: 10.1080/07388551.2020.1808583 -
Bioinformatics (Oxford, England) Nov 2021Ligand-receptor (LR) network analysis allows the characterization of cellular crosstalk based on single cell RNA-seq data. However, current methods typically provide a...
MOTIVATION
Ligand-receptor (LR) network analysis allows the characterization of cellular crosstalk based on single cell RNA-seq data. However, current methods typically provide a list of inferred LR interactions and do not allow the researcher to focus on specific cell types, ligands or receptors. In addition, most of these methods cannot quantify changes in crosstalk between two biological phenotypes.
RESULTS
CrossTalkeR is a framework for network analysis and visualization of LR interactions. CrossTalkeR identifies relevant ligands, receptors and cell types contributing to changes in cell communication when contrasting two biological phenotypes, i.e. disease versus homeostasis. A case study on scRNA-seq of human myeloproliferative neoplasms reinforces the strengths of CrossTalkeR for characterization of changes in cellular crosstalk in disease.
AVAILABILITY AND IMPLEMENTATION
CrosstalkeR is an R package available at: Github: https://github.com/CostaLab/CrossTalkeR.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Gene Expression Profiling; Humans; Ligands; Sequence Analysis, RNA; Single-Cell Analysis; Software
PubMed: 35032393
DOI: 10.1093/bioinformatics/btab370 -
Nature Communications Sep 2023Many orphan G protein-coupled receptors (GPCRs) remain understudied because their endogenous ligands are unknown. Here, we show that a group of class A/rhodopsin-like...
Many orphan G protein-coupled receptors (GPCRs) remain understudied because their endogenous ligands are unknown. Here, we show that a group of class A/rhodopsin-like orphan GPCRs including GPR61, GPR161 and GPR174 increase the cAMP level similarly to fully activated D1 dopamine receptor (D1R). We report cryo-electron microscopy structures of the GPR61‒G, GPR161‒G and GPR174‒G complexes without any exogenous ligands. The GPR174 structure reveals that endogenous lysophosphatidylserine (lysoPS) is copurified. While GPR174 fails to respond to exogenous lysoPS, likely owing to its maximal activation by the endogenous ligand, GPR174 mutants with lower ligand binding affinities can be specifically activated by lysoPS but not other lipids, in a dose-dependent manner. Moreover, GPR174 adopts a non-canonical G coupling mode. The structures of GPR161 and GPR61 reveal that the second extracellular loop (ECL2) penetrates into the orthosteric pocket, possibly contributing to constitutive activity. Our work definitively confirms lysoPS as an endogenous GPR174 ligand and suggests that high constitutive activity of some orphan GPCRs could be accounted for by their having naturally abundant ligands.
Topics: Ligands; Cryoelectron Microscopy; Signal Transduction; Receptors, Dopamine D1
PubMed: 37737235
DOI: 10.1038/s41467-023-41654-3 -
Journal of Chemical Information and... Sep 2022Herein, we introduce a new strategy to estimate binding free energies using end-state molecular dynamics simulation trajectories. The method is adopted from linear...
Herein, we introduce a new strategy to estimate binding free energies using end-state molecular dynamics simulation trajectories. The method is adopted from linear interaction energy (LIE) and ANI-2x neural network potentials (machine learning) for the atomic simulation environment (ASE). It predicts the single-point interaction energies between ligand-protein and ligand-solvent pairs at the accuracy of the wb97x/6-31G* level for the conformational space that is sampled by molecular dynamics (MD) simulations. Our results on 54 protein-ligand complexes show that the method can be accurate and have a correlation of = 0.87-0.88 to the experimental binding free energies, outperforming current end-state methods with reduced computational cost. The method also allows us to compare BFEs of ligands with different scaffolds. The code is available free of charge (documentation and test files) at https://github.com/otayfuroglu/deepQM.
Topics: Ligands; Molecular Dynamics Simulation; Protein Binding; Proteins; Thermodynamics
PubMed: 35972783
DOI: 10.1021/acs.jcim.2c00601 -
Molecular Cell Sep 2022Kleist et al. combine NMR spectroscopy and residue contact network analysis to identify a potential allosteric network in CXCR7, a β-arrestin-biased chemokine...
Kleist et al. combine NMR spectroscopy and residue contact network analysis to identify a potential allosteric network in CXCR7, a β-arrestin-biased chemokine receptor, which links the extracellular ligand-binding pocket and the intracellular transducer-coupling region through the receptor transmembrane core.
Topics: Ligands; Signal Transduction; beta-Arrestins
PubMed: 36113411
DOI: 10.1016/j.molcel.2022.08.020 -
Drug Discovery Today Dec 2016Computational functional group mapping (cFGM) is emerging as a high-impact complement to existing widely used experimental and computational structure-based drug... (Review)
Review
Computational functional group mapping (cFGM) is emerging as a high-impact complement to existing widely used experimental and computational structure-based drug discovery methods. cFGM provides comprehensive atomic-resolution 3D maps of the affinity of functional groups that can constitute drug-like molecules for a given target, typically a protein. These 3D maps can be intuitively and interactively visualized by medicinal chemists to rapidly design synthetically accessible ligands. Given that the maps can inform selection of functional groups for affinity, specificity, and pharmacokinetic properties, they are of utility for both the optimization of existing drug candidates and creating novel ones. Here, I review recent advances in cFGM with emphasis on the unique information content in the approach that offers the potential of broadly facilitating structure-based ligand design.
Topics: Computational Biology; Drug Discovery; Ligands; Structure-Activity Relationship
PubMed: 27393487
DOI: 10.1016/j.drudis.2016.06.030 -
Molecules (Basel, Switzerland) May 2023Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor belonging to the basic helix-loop-helix (bHLH)/per-Arnt-sim (PAS) superfamily, is traditionally... (Review)
Review
Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor belonging to the basic helix-loop-helix (bHLH)/per-Arnt-sim (PAS) superfamily, is traditionally known to mediate xenobiotic metabolism. It is activated by structurally diverse agonistic ligands and regulates complicated transcriptional processes through its canonical and non-canonical pathways in normal and malignant cells. Different classes of AhR ligands have been evaluated as anticancer agents in different cancer cells and exhibit efficiency, which has thrust AhR into the limelight as a promising molecular target. There is strong evidence demonstrating the anticancer potential of exogenous AhR agonists including synthetic, pharmaceutical, and natural compounds. In contrast, several reports have indicated inhibition of AhR activity by antagonistic ligands as a potential therapeutic strategy. Interestingly, similar AhR ligands exert variable anticancer or cancer-promoting potential in a cell- and tissue-specific mode of action. Recently, ligand-mediated modulation of AhR signaling pathways and the associated tumor microenvironment is emerging as a potential approach for developing cancer immunotherapeutic drugs. This article reviews advances of AhR in cancer research covering publication from 2012 to early 2023. It summarizes the therapeutic potential of various AhR ligands with an emphasis on exogenous ligands. It also sheds light on recent immunotherapeutic strategies involving AhR.
Topics: Receptors, Aryl Hydrocarbon; Ligands; Signal Transduction
PubMed: 37241719
DOI: 10.3390/molecules28103978