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Journal of the American Chemical Society Sep 2022We report the synthesis of molecular prime and composite knots by social self-sorting of 2,6-pyridinedicarboxamide (pdc) ligands of differing topicity and...
We report the synthesis of molecular prime and composite knots by social self-sorting of 2,6-pyridinedicarboxamide (pdc) ligands of differing topicity and stereochemistry. Upon mixing achiral monotopic and ditopic pdc-ligand strands in a 1:1:1 ratio with Lu(III), a well-defined heteromeric complex featuring one of each ligand strand and the metal ion is selectively formed. Introducing point-chiral centers into the ligands leads to single-sense helical stereochemistry of the resulting coordination complex. Covalent capture of the entangled structure by ring-closing olefin metathesis then gives a socially self-sorted trefoil knot of single topological handedness. In a related manner, a heteromeric molecular granny knot (a six-crossing composite knot featuring two trefoil tangles of the same handedness) was assembled from social self-sorting of ditopic and tetratopic multi-pdc strands. A molecular square knot (a six-crossing composite knot of two trefoil tangles of opposite handedness) was assembled by social self-sorting of a ditopic pdc strand with four ()-centers and a tetratopic strand with two ()- and six ()-centers. Each of the entangled structures was characterized by H and C NMR spectroscopy, mass spectrometry, and circular dichroism spectroscopy. The precise control of composition and topological chirality through social self-sorting enables the rapid assembly of well-defined sequences of entanglements for molecular knots.
Topics: Alkenes; Ligands; Magnetic Resonance Spectroscopy
PubMed: 36067448
DOI: 10.1021/jacs.2c07682 -
Annual Review of Cell and Developmental... Oct 2023Cell-cell communication is critical for the development and function of multicellular organisms. A crucial means by which cells communicate with one another is physical... (Review)
Review
Cell-cell communication is critical for the development and function of multicellular organisms. A crucial means by which cells communicate with one another is physical interactions between receptors on one cell and their ligands on a neighboring cell. ligand:receptor interactions activate the receptor, ultimately leading to changes in the fate of the receptor-expressing cells. Such signaling is known to be critical for the functions of cells in the nervous and immune systems, among others. Historically, interactions are the primary conceptual framework for understanding cell-cell communication. However, cells often coexpress many receptors and ligands, and a subset of these has been reported to interact in and profoundly impact cell functions. interactions likely constitute a fundamental, understudied regulatory mechanism in cell biology. Here, I discuss how interactions between membrane receptors and ligands regulate immune cell functions, and I also highlight outstanding questions in the field.
Topics: Ligands; Cell Communication; Signal Transduction
PubMed: 37339682
DOI: 10.1146/annurev-cellbio-120420-103941 -
Soft Matter Jun 2021Simultaneous binding of a divalent ligand to two identical monovalent molecules is a widespread phenomenon in biology and chemistry. Here, we describe how two such...
Simultaneous binding of a divalent ligand to two identical monovalent molecules is a widespread phenomenon in biology and chemistry. Here, we describe how two such monovalent molecules B bind to a divalent ligand AA to form the intermediate and final complexes AA·B and AA·B2. Cases wherein the total concentration [AA]T is either much larger or much smaller than the total concentration [B]T have been studied earlier, but a systematic description of comparable concentrations [AA]T and [B]T is missing. Here, we present numerical and analytical results for the concentrations [AA·B] and [AA·B2] for the entire range 0 < [B]T/[AA]T < ∞. Specifically, we theoretically study three types of experimental procedures: dilution of AA and B at fixed [B]T/[AA]T, addition of AA at fixed [B]T, and addition of B at fixed [AA]T. When [AA]T and [B]T are comparable, the concentrations of free ligands and molecules both decrease upon binding. Such depletion is expected to be important in cellular contexts, e.g., in antigen detection and in coincidence detection of proteins or lipids.
Topics: Biophysical Phenomena; Cations, Divalent; Ligands
PubMed: 33961000
DOI: 10.1039/d1sm00070e -
Inorganic Chemistry Sep 2022The complex [TEA][Tp*Mo(O)(SBMOPP)] () [TEA = tetraethylammonium, Tp* = tris(3,5-dimethylpyrazolyl)hydroborate, and BMOPP = 6-(3-butynyl-2-methyl-2-ol)-2-pivaloyl...
The complex [TEA][Tp*Mo(O)(SBMOPP)] () [TEA = tetraethylammonium, Tp* = tris(3,5-dimethylpyrazolyl)hydroborate, and BMOPP = 6-(3-butynyl-2-methyl-2-ol)-2-pivaloyl pterin] is a structural analogue of the molybdenum cofactor common to all pyranopterin molybdenum enzymes because it possesses a pyranopterin-ene-1,2-dithiolate ligand (SBMOPP) that exists primarily in the ring-closed pyrano structure as a resonance hybrid of ene-dithiolate and thione-thiolate forms. Compound , the protonated [Tp*Mo(O)(SBMOPP-H)] () and one-electron-oxidized [Tp*Mo(O)(SBMOPP)] [] species have been studied using a combination of electrochemistry, electronic absorption, and electron paramagnetic resonance (EPR) spectroscopy. Additional insight into the nature of these molecules has been derived from electronic structure computations. Differences in dithiolene C-S bond lengths correlate with relative contributions from both ene-dithiolate and thione-thiolate resonance structures. Upon protonation of to form , large spectroscopic changes are observed with transitions assigned as Mo(xy) → pyranopterin metal-to-ligand charge transfer and dithiolene → pyranopterin intraligand charge transfer, respectively, and this underscores a dramatic change in electronic structure between and . The changes in electronic structure that occur upon protonation of are also reflected in a large >300 mV increase in the Mo(V/IV) redox potential for , resulting from the greater thione-thiolate resonance contribution and decreased charge donation that stabilize the Mo(IV) state in with respect to one-electron oxidation. EPR spin Hamiltonian parameters for one-electron-oxidized and uncyclized [Tp*Mo(O)(SBDMPP)] [] [BDMPP = 6-(3-butynyl-2,2-dimethyl)-2-pivaloyl pterin] are very similar to each other and to those of [Tp*MoO(bdt)] (bdt = 1,2-ene-dithiolate). This indicates that the dithiolate form of the ligand dominates at the Mo(V) level, consistent with the demand for greater S → Mo charge donation and a corresponding increase in Mo-S covalency as the oxidation state of the metal is increased. Protonation of represents a simple reaction that models how the transfer of a proton from neighboring acidic amino acid residues to the Mo cofactor at a nitrogen atom within the pyranopterin dithiolene (PDT) ligand in pyranopterin molybdenum enzymes can impact the electronic structure of the Mo-PDT unit. This work also illustrates how pyran ring-chain tautomerization drives changes in resonance contributions to the dithiolene chelate and may adjust the reduction potential of the Mo ion.
Topics: Electron Spin Resonance Spectroscopy; Ligands; Molybdenum; Pterins; Thiones
PubMed: 36000991
DOI: 10.1021/acs.inorgchem.2c01234 -
Proteins Jun 2022The Kaposi's sarcoma-associated herpesvirus protease is essential for virus maturation. This protease functions under allosteric regulation that establishes its...
The Kaposi's sarcoma-associated herpesvirus protease is essential for virus maturation. This protease functions under allosteric regulation that establishes its enzymatic activity upon dimerization. It exists in equilibrium between an inactive monomeric state and an active, weakly associating, dimeric state that is stabilized upon ligand binding. The dynamics of the protease dimer and its monomer were studied using the Gaussian network model and the anisotropic network model , and its role in mediating the allosteric regulation is demonstrated. We show that the dimer is composed of five dynamical domains. The central domain is formed upon dimerization and composed of helix five of each monomer, in addition to proximal and distal domains of each monomer. Dimerization reduces the mobility of the central domains and increases the mobility of the distal domains, in particular the binding site within them. The three slowest ANM modes of the dimer assist the protease in ligand binding, motion of the conserved Arg142 and Arg143 toward the oxyanion, and reducing the activation barrier for the tetrahedral transition state by stretching the bond that is cleaved by the protease. In addition, we show that ligand binding reduces the motion of helices α1 and α5 at the interface and explain how ligand binding can stabilize the dimer.
Topics: Allosteric Regulation; Binding Sites; Dimerization; Herpesvirus 8, Human; Ligands
PubMed: 35084062
DOI: 10.1002/prot.26307 -
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 -
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