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GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several psychiatric disorders.sup.1,2. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric G.sub.s protein.sup.2, but it is unclear how GPR52 and G.sub.s couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a G.sub.s-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR52.sup.3. A fully active state is achieved when G.sub.s is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52. Structures of the orphan G-protein-coupled receptor GPR52 in ligand-free, G-protein-coupled and ligand-bound states reveal that extracellular loop 2 occupies the orthosteric binding pocket and functions as a built-in agonist to activate the receptor., Author(s): Xi Lin [sup.1] [sup.2] [sup.3] [sup.4] , Mingyue Li [sup.2] [sup.3] [sup.4] , Niandong Wang [sup.1] [sup.2] [sup.3] [sup.4] , Yiran Wu [sup.1] , Zhipu Luo [sup.5] , Shimeng [...]

Human [GABA.sub.B] (γ-aminobutyric acid class B) receptor is a G-protein-coupled receptor central to inhibitory neurotransmission in the brain. It functions as an obligatory heterodimer of the subunits GBR1 and GBR2. Here we present the crystal structures of a heterodimeric complex between the extracellular domains of GBR1 and GBR2 in the apo, agonist-bound and antagonist-bound forms. The apo and antagonist-bound structures represent the resting state of the receptor; the agonist-bound complex corresponds to the active state. Both subunits adopt an open conformation at rest, and only GBR1 closes on agonist-induced receptor activation. The agonists and antagonists are anchored in the interdomain crevice of GBR1 by an overlapping set of residues. An antagonist confines GBR1 to the open conformation of the inactive state, whereas an agonist induces its domain closure for activation. Our data reveal a unique activation mechanism for [GABA.sub.B] receptor that involves the formation of a novel heterodimer interface between subunits., GABA is the predominant inhibitory neurotransmitter in the central nervous system. Metabotropic [GABA.sub.B] receptor is a G-protein-coupled receptor that mediates slow and prolonged synaptic inhibition through [G.sub.i] or [G.sub.o] protein [...]

Delta-like 4 (DII4) is a transmembrane ligand for Notch receptors that is expressed in arterial blood vessels and sprouting endothelial cells. Here we show that DII4 regulates vessel branching during development by inhibiting endothelial tip cell formation. Heterozygous deletion of dII4 or pharmacological inhibition of Notch signaling using [gamma]-secretase inhibitor revealed a striking vascular phenotype, with greatly increased numbers of filopodia- extending endothelial tip cells and increased expression of tip cell marker genes compared with controls. Filopodia extension in dII[4.sup.+/-] retinal vessels required the vascular growth factor VEGF and was inhibited when VEGF signaling was blocked. Although VEGF expression was not significantly altered in dII[4.sup.+/-] retinas, dII[4.sup.+/-] vessels showed increased expression of VEGF receptor 2 and decreased expression of VEGF receptor 1 compared with wildtype, suggesting they could be more responsive to VEGF stimulation. In addition, expression of dII4 in wild-type tip cells was itself decreased when VEGF signaling was blocked, indicating that dII4 may act downstream of VEGF as a 'brake' on VEGF-mediated angiogenic sprouting. Taken together, these data reveal DIM as a negative regulator of vascular sprouting and vessel branching that is required for normal vascular network formation during development. angiogenesis | vascular development | VEGF | sprouting | guidance

The two-state BT model, that considers the possibility of redistribution of population from the force-free bound state to the force stabilized bound state, is used to investigate the energy landscape underlying the catch-slip transition. The model correctly predicts the absence of catch bonds in the binding dynamics of antibodies to selectins and is used to solve to energy landscape parameters characterizing adhesive interactions of P- and L-selectin complexes with sPSGL-I and endoglycan and the antibody DREG56.

A new model is developed and utilized for investigating the salt concentration dependence of the binding free energy by an analytic treatment of the Coulombic end effect (CEE) for the nonspecific binding of various cationic ligands and proteins with small nucleic acids. The analysis shows that CEE is highly responsible for the reductions in the salt dependence of the melting temperature for the transitions and also helps in determining the binding constants of the interactions.

Soluble metal-ligand complexes are useful as catalysts for many organic reactions. The large number of metals and ligands available suggests a combinatorial approach to catalyst discovery. Carrying out reactions in very small (microliter) volumes in capillaries has many advantages in this regard, including material conservation, isolation from the atmosphere, and ease of transport of species by using pressure-induced flow. We have developed a capillary reactor in which separate zones of catalyst and reactants are combined and react. Zones are loaded serially into the capillary reactor from an autosampler, they react in parallel in the capillary reactor (at elevated temperature) and are ejected serially and under computer control for analysis by online GC. Offline analysis following sample collection is also possible. The Stille crosscoupling reaction has been the focus of our recent activity. Known palladium-based precatalysts and phosphine or arsine ligands were screened to validate the approach taken here. The results largely agree with results obtained by traditional organic synthesis, validating the method. The throughput of the nonoptimized system is over two 5-h reactions/h. For example, 40 5-h reactions examining the effect of catalyst loading were performed in 2 9-h runs requiring a total of 2 h of operator time.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine with potential therapeutic value against cancers because of its selective cytotoxicity to many transformed, but not normal, cells. The 'decoy receptors' TRAIL-R3 (TR3) and TRAIL-R4 (TR4) were believed to negatively regulate TRAIL-induced cytotoxicity by competing for ligand binding with TRAIL-R1 (TR1) and TRAIL-R2 (TR2). Here, we show that inhibition of TRAIL-induced apoptosis by TR4 critically depends on its association with TR2 via the NH2-terminal preligand assembly domain overlapping the first partial cysteine-rich domain of both receptors. By contrast, ligand binding by TR4 is dispensable for its apoptosis inhibitory function, thereby excluding the possibility that TR4 was a 'decoy' to inhibit apoptosis by binding up TRAIL. In primary CD[8.sup.+] T cells, which express only TR2 and TR4 and are resistant to TRAIL-induced apoptosis, stimulation with phorbol myristate acetate abrogated the ligand-independent interaction between TR2 and TR4 and enhanced their sensitivity to TRAIL-induced apoptosis. Hence, whereas most TNF receptors normally form only homotrimeric complexes, the preligand assembly domains in TR2 and TR4 permit mixed complex formation as a means to regulate apoptosis induction. We propose that TR4 is a 'regulatory' rather than 'decoy' receptor that inhibits apoptosis signaling by TRAIL through this previously uncharacterized ligand-independent mechanism. decoy receptors

The structural characterization and solution thermodynamic properties of iron complexes of two of the heteropodans ligands, based on hydroxypyridinonate (HOPO) and other ligands, that are therapeutic agents for ferric ion sequestration are reported. The ligands that are described are part of a new class of heteropodate ligands, which exploit the various chelating properties of several binding units within a single tripodal ligand and allow for systematic variation of the properties for medical or other applications.

The preparation of a new series of mixed-ligand oxorhenium complexes with ligands containing the SNN donor set (general formula RCH(sub 2)(CH(sub 2)NHCH(sub 2)CH(sub 2)SH, where R = N(N2H5)(sub 2), pyrrolidin-1-yl, or N[CH(CH3)](sub 2)) and monodentate thiols as coligands is presented. When R = N[CH(CH3)](sub 2), the tertiary nitrogen of the ligand does not participate in the coordination sphere of the metal, a novel type of '2+1+1' [SN][S][S] complex was obtained and X-ray and NMR assignments were performed for these mixed-ligand complexes.

The variation and control of coordination modes and properties of the Cu(II) complexes with 1,5-diazacyclooctane (DACO) are achieved by altering the pendant donors on the framework of diazamesocycle. The nature of the functional pendant arms was the determining factors governing the structure and magnetic properties of the Cu(II) complexes.

The synthesis and the protonation and chelation behavior of a cyclen-based ligand containing trans-acetate and trans-methylenephosphonate pendant groups, [H.sub.6]DO2ASP is described. Activation enthalpy and entropy values for enantiomerization process suggest that Ln(DO2A2P) complexes are less rigid than the corresponding DOTP complexes.

A combination of experimental and theoretical studies was performed to determine the relationship between structure and photophysical properties of [Ru.sup.II] bis-tridentate complexes containing bipyridyl-alkanylene-pyridyl ligands. The large difference observed in the excited-state lifetimes for homoleptic [Ru.sup.II] complexes are strongly influenced by steric interactions on the ligand field strength.

Constrained versions of anabasine, a naturally occurring nAChR ligand was designed and synthesized to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the [alpha]4[beta]2 and [alpha]7 subtype receptors. All compounds synthesized exhibited high affinity of the [alpha]4[beta]2 nAChR subtype, a subset bound with high affinity for the [alpha]7 receptor subtype, selectively over the [alpha]3[beta]4 receptor subtype.

The significance of the ancillary ligand N,N-dimethylaminoethanol in the sensitization of [Eu.sup.III] and [Tb.sup.III] luminescence in dimeric [beta]-diketonates is discussed. The thin films of the discussed compounds are shown to be extremely useful in various electroluminescent devices.

A novel method is described for the efficient discovery of new types of minor actinide (MA) ligands, which is based on the unique combination of tea bag split pool combinatorial chemistry and screening based on the inherent radioactivity of the complexed cations. The method has also allowed the competitive screening of multiple nuclides that can be quantified by their radioactive emission spectrum.

The synthesis of a compound featuring the terminally bound GaI ligand is described, whish has represented the first experimental realization of a valence isoelectronic group 13/group 17 analogue of CO and [N.sub.2]. The coordinative trapping of the GaI and its electronic structure are examined.

The article discusses the benefits of using the density functional theory for studying the geometries and the electronic structures of the metal salen complexes of 3[d.sup.0]-metals. The method is shown to be better than the other conventional methods for studying the cases of strong nondynamical correlation.

An in silico methodology is described that has diminished the effects of structural uncertainty and has allowed for more inclusive representation of a potential docking interaction with exogenous ligands. The virtual screening approach has proved applicable in the search for novel small molecule agonists and antagonists of other G protein-coupled receptors (GPCRs).

A highly ordered molecular-based material is described by using a hierarchical approach where the stronger metal-organic coordination has governed the order in the direction of growth and the weaker, sterically demanding, [pi]-[pi] interactions have tuned the lateral stability. The interactions are shown to be interdependent as the in-plane ordering has induced structural regularity in the axial direction.

The implementation of a new strategy for labeling the exterior surface of a virus capsid is described by considering the compatibility of the protein particles with glycosyltransferase enzymes and chemoenzymatic reaction conditions. The resulting structures have multivalent arrays of glycan ligands favorable for binding to a cell surface glycan receptor in a highly specific manner.

The simple preparation of new B/Si bidentate Lewis acids, o-(fluorosilyl)(dimesitylboryl)-benzenes and their ability to bind fluoride ion by forming a [mu]-fluoro bridge is reported. The modification of substituents on the boron and silicon centers might lead to diversified B/Si bidentate Lewis acids for selective binding of a particular Lewis base, such as detection of a specified halide ion.

Ab initio calculations and Car-Parrinello molecular dynamics simulations were used to determine the coordination and geometry of Al in aqueous AlEDTA ( where Al = aluminum, EDTA = ethylenediaminetetraacetate). The results suggest that AlEDTA favors Al in octahedral coordination in aqueous solution which is also supported by X-ray measurement for the strong chelating nature of the metal-organic complex in aqueous solution.

Single-nucleotide resolution SHAPE chemistry is employed to analyze the effects of two ligands, [Mg.sup.2+] and tobramycin, on the folding of S. cerevisiae [tRNA.sup.Asp] transcripts. The findings provide insight into structural consequences of ligand binding to RNA at single nucleotide resolution which contribute to complex RNA folding landscapes as a function of ligand environment.

The synthesis of chiral biisoquinoline-based tricyclic chiral diaminocarbene ligands (BIQ) and their Pd and Cu complexes is reported. The cyclohexyl-BIQ-copper complex is an efficient catalyst for enantioselective [S.sub.N]2' allylic alkylation with Grignard reagents.

The synthesis and characterization of the first thiosemicarbazone-lumazine hybrid ligand is described. The study has shown the ability of this ligand to form mono- and dinuclear species with different coordination modes due to the nonrigidity of the relative disposition of thiosemicarbazone and lumazine moieties.

The amphoteric 5-(4-cyanophenyl)dipyrrin ligand, which has offered three distinct states (cationic, neutral and anionic), is used for the formation of a one-dimensional (1-D) hydrogen-bonded network in its protonated form and both homo- and heterobinuclear metallamacrocycles. The cationic state has acted as a chelate for Co and has formed an Ag-[pi] interaction, which has led to a heteronuclear metallamacrocycle.

The triple-exponential fluorescence [delta]-response function is determined for the photophysical model of successive complexation between ligand and analyte. The studies have shown that zero values for exchange rates and spectral parameters linked to excitation and emission have led to non-controllable or non-observable systems.

The factors controlling the resolution process of chiral, tetrahedral [M.sub.4][L.sub.6] metal-ligand hosts are examined. The exchange of the resolving S-[nic.sup.+] agents for chiral guests and the stability of the chiral supramolecular framework have shown the robustness of the structure, while the ability to produce resolved [M.sub.4][I.sub.6] salts of non-binding guests is vital for developing the asymmetrically influenced encapsulated chemistries.

Monodentate phosphoramidites are a highly versatile class of ligands, which are used for asymmetric hydrogenation. The ligands are highly modular and easy to synthesize enabling their robotic parallel synthesis.

The design and synthesis of a series of modular ligands based on poly(ethylene glycol) (PEG) coupled with functional terminal groups to promote water-solubility and biocompatibility of quantum dots (QDs), are described. The covalent coupling technique has opened up an easy access to a variety of biological entities and has provided additional options for designing biological assays.

The electrochemical behavior of an aminotrithioether ligand is explained. The analysis reveals that the ligand undergoes oxidation and leads to C-C bond formation on being interacted with copper, Cu(II).

A novel path is described for assembling the hybrid materials containing the inorganic polymeric Si-O network and organic polymeric chains. The photoluminescence properties of these materials have shown that the ternary rare-earth/inorganic/organic polymeric hybrids present stronger luminescent intensities and higher luminescent quantum efficiencies than the binary rare-earth/inorganic polymeric hybrids.

A study reports that fluorinated phenoxide could be used to form stable, soluble compounds of Eu(II) and Eu(III) as well as a heterovalent dimer. Dative Ln-F interactions were noted with Eu(II) ions while Eu(III) ions were observed to adopt terminal phenoxide ligations and since phenoxides are soluble in apolar media, they are potentially useful as capping reagents in lanthanide cluster chemistry.

The different methods used for computing labile metal-ligand complexes, which are suitable for an iterative computer solution, are illustrated. The ligand function has allowed students to relegate otherwise tedious iterations to a computer, while retaining complete control over what is calculated.

A computational examination of the nature of the interaction between the affinity ligand and the agarose support to which it was bound through spacers of varying length and chemical nature is done through molecular dynamics. It is demonstrated that a change in the spacer properties could decide a change of the stable structure of the ligand with respect to the support and that if a support is not held fixed through restraints, the interaction forces between vicinal ligands will determine a major conformational change of the system.

A combination of density functional theory (DFT) calculations and vibrational circular dichroism (VCD) measurements are applied to assign absolute configuration to the enantiomers of borane adduct of aminophosphine tert-butyl(dimethlamino)phenylphospine. The DFT generated structure of (+)-tert-butyl(dimethlamino)phenylphospine-borane complex is found to correspond to the most stable conformation in solution.

The ability of peptide nucleic acids (PNAs) to introduce a site-specific psoralen photoadduct for the purpose of gene modification is investigated. The results demonstrate the ability of bis-PNAs conjugated with psoralen to mediate site-specific gene modification and also support the development of PNAs as tools for gene-targeting applications.

A study is conducted to develop minor-groove binders that bind the double binding motifs cooperatively. The new bidentate ligands are designed by connecting two Hoechst 33258 units with a polyether linker for cooperative binding with two remote A3T3 sites of DNA.

A novel macrocyclic DOTA like ligand is evaluated to study the therapy, which contains a monoamide bis(phosphonic acid) that targets the bone group. The result shows that the amide bis(phosphonate) moiety is the sole element responsible to bind the complex to hydroxyapatite.

An establishment that V-I and V-II contain the polypeptide of Bacillus thermoproteolyticus ferredoxin (BtFd) associated with acyl carrier protein (ACP) and with coenzyme A (CoA), respectively, and that V-III is a BtFd dimer linked by a disulfide bond is presented. The crystal structure of the BtFd-CoA complex (V-II) determined at 1.6-angstrom resolution reveal that each of the four complexes in the crystallographic asymmetric unit possesses a [3Fe-4S] cluster that is coordinated by Cys(super 11), Cys(super 17), and Cys(super 61).

The studies show that wild-type and mutant hemoglobins can adopt a range of T-like quaternary structures, the T (sub high) structures, when quaternary-T deoxyhemoglobin is exposed to ligand in the crystalline state. The analysis suggests a more extended energy transduction pathway in which ligand-induced beta1-heme movement triggers tertiary changes in the beta1 subunit.