Modeling the interactions of a peptide-major histocompatibility class I ligand with its receptors. I. Recognition by two αβ T cell receptors

A three-dimensional model of the complex between an Influenza Hemagglutinin peptide, Ha_255–262, and its restricting element, the mouse major histocompatibility complex (MHC) class I molecule, K^k, was built by homology modeling and subsequently refined by simulated annealing and restrained molecular dynamics. Next, three-dimensional models of two different T cell receptors (TCRs) both specific for the Ha_255–262/K^k complex were generated based on previously published TCR X-ray structures. Finally, guided by the recently published X-ray structures of ternary TCR/peptide/MHC-I complexes, the TCR models were successfully docked into the Ha_255–262/K^k model. We have previously used a systematic and exhaustive panel of 144 single amino acid substituted analogs to analyze both MHC binding and T cell recognition of the parental viral peptide. This large body of experimental data was used to evaluate the models. They were found to account well for the experimentally obtained data, lending considerable support to the proposed models and suggesting a universal docking mode for TCRs to MHC-peptide complexes. Such models may also be useful in guiding future rational experimentation.     

Different binding orientations for the same agonist at homologous receptors: a lock and key or a simple wedge?

Using unnatural amino acid mutagenesis, the binding site for serotonin at the novel Caenorhabditis elegans receptor MOD-1 has been probed. As with the closely related serotonin receptor 5-HT3, MOD-1 makes use of a strong cation-pi interaction between the ammonium of serotonin and the indole side chain of a tryptophan. However, the specific Trp used by MOD-1 is different from that used for 5-HT3 (and the nAChR), aligning with a residue more than 40 amino acids distant in sequence space and on a different "loop" of the agonist binding site. This suggests a significant rearrangement of the ligand on binding these two closely related receptors. It is suggested that, unlike enzymes, receptors and other signaling molecules may need only to deliver an agonist to a general binding region, rather than establishing precise drug-receptor interactions.     

Alkaloids ofArundo donax. IV. donaxanine — a new pyrrolidine alkaloid fromArundo donax

The new pyrrolidone alkaloid donaxanine, C₁₂H₁₄N₂O₂, has been isolated from Arundo donax. Its structure has been shown by chemical transformations and a study of its IR, mass, and PMR spectra as spiro[(N-methylpyrrolidin-2-one)-3,4-(3,1-benzoxazine).Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent, fax (3712) 89 14 75. Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 728–730, September–October, 1995. Original article submitted June 5, 1995.     

The origin of cooperativity in double-wheel receptors. Freezing of internal rotation or ligand-induced torsional strain?

A model is proposed for the homotropic cooperative binding of a ditopic ligand to a double-wheel receptor with the aim of understanding the origin of cooperativity. Application of the model to the case of Ce(IV) bisporphyrinate double-decker complexes indicates that cooperativity is mainly due to ligand-induced torsional strain. [structure: see text]     

Identification of a novel cannabimimetic phenylacetylindole, cannabipiperidiethanone, as a designer drug in a herbal product and its affinity for cannabinoid CB₁ and CB₂ receptors

A new cannabimimetic phenylacetylindole (cannabipiperidiethanone, 1) has been found as an adulterant in a herbal product which contains two other known synthetic cannabinoids, JWH-122 and JWH-081, and which is distributed illegally in Japan. The identification was based on analyses using GC-MS, LC-MS, high-resolution MS and NMR. Accurate mass spectrum measurement showed the protonated molecular ion peak of 1 at m/z 377.2233 [M+H]? and the molecular formula of 1 was C??H??N?O?. Both mass and NMR spectrometric data revealed that 1 was 2-(2-methoxyphenyl)-1-{1-[(1-methylpiperidin-2-yl)methyl]-1H-indol-3-yl}ethanone. Compound 1 has a mixed structure of known cannabimimetic compounds: JWH-250 and AM-2233. Namely, the moiety of phenylacetyl indole and N-methylpiperidin-2-yl-methyl correspond to the structure of JWH-250 and AM-2233, respectively. However, no synthetic, chemical or biological information about 1 has been reported. A binding assay of compound 1 to cannabinoid receptors revealed that 1 has affinity for the CB? and CB? (IC??=591, 968 nM, respectively) receptors, and shows 2.3- and 9.4-fold lower affinities than those of JWH-250. This is the first report to identify cannabimimetic compound (1) as a designer drug and to show its binding affinity to cannabinoid receptors.     

S. Wageh a,*, Ahmed A. Al‐Ghamdi a,Rashida Jafer a,Xin Li b,#, Peng Zhang c

太阳能是最丰富的清洁和可再生能源,光催化技术在太阳能利用中具有很大潜力,这有赖于高效半导体光催化剂的设计制备.然而,单一光催化剂效率很低,主要是光生电子和空穴的强库伦吸引力导致它们快速复合.此外,单一光催化剂也很难同时具有宽光谱吸收和足够的氧化还原能力.为了解决这一问题,构建异质结光催化剂成为一种有效途径,因为它可以实现光生电子和空穴在空间上的有效分离.针对传统的II型和Z型异质结在动力学和热力学方面的缺陷, 2019年由武汉理工大学余家国教授团队提出梯形异质这一新型异质结概念.对于II型异质结,热力学和动力学分析表明光生载流子的转移机理不正确.热力学和动力学分析表明光生载流子的转移机理不正确.而Z型异质结系统主要包括传统、全固态和直接Z型异质结三种类型.对于前两种异质结,它们的界面电子转移存在理论问题.传统Z型异质结利用氧化还原电对,而电子受体和给体更容易从与其具有较大的电势差的半导体接受或给予电子.全固态Z型异质结利用导体,比如导电金属或碳材料,取代氧化还原电对,从而使其应用范围由液态扩展到固态.然而通过进一步分析,它的电荷传输也有漏洞.首先,界面的肖特基势垒抑制电荷持续传输,此外,全固态Z型异质结中的导体与传统Z型中氧化还原电对的作用如出一辙.因此,传统Z型的问题在这里也依旧存在.总的来说, II型、传统和全固态Z型都面临相同的问题,就是光生电子和空穴拥有较弱的还原和氧化能力,而S型异质结则与它们截然不同.该异质结由氧化型和还原型光催化剂组成,内建电场、能带弯曲和库仑力三大作用促使氧化型的光生电子与还原型的光生空穴复合,同时阻止氧化型的光生空穴与还原型的光生电子转移.最终,电子和空穴分别具有高的还原和氧化能力.由于其优越性, S型异质结在各种光催化应用中引起了广泛的兴趣,包括产氢、二氧化碳还原、污染物降解和灭菌等领域.而S型异质结机理可以用X射线光电子能谱、电子顺磁共振和原子力显微镜进行表征.S型异质结崭露头角,未来发展可期.     

Monepaloside K,a New Triterpenoid Saponin from Morina nepalensis var.alba Hand.—Mazz.

One new triterpenoid saponin,monepaloside K(1) was isolated from the water-soluble part of the whole plant of a famous Tibetan medicinal herb,morina neplaensis var. alba Hand.-Mazz.Its structure was determined to be 3-O-α-L-arabinopyranosyl-(1→3)-β-D-xylopyranosyl siaresinolic acid on the basis of spectroscopic evidences,especially 2D NMR techniques.     

Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors

Genetic deficiency of Jak3 leads to abrogation of signal transduction through the common gamma chain (γc) and thus to immunodeficiency suggesting that specific inhibition of Jak3 kinase may result in immunosuppression. Jak1 cooperates with Jak3 in signaling through γc-containing receptors. Unexpectedly, a Jak3-selective inhibitor was less efficient in abolishing STAT5 phosphorylation than pan-Jak inhibitors. We therefore explored the roles of Jak1 and Jak3 kinase functionality in signaling using a reconstituted system. The presence of kinase-inactive Jak1 but not kinase-inactive Jak3 resulted in complete abolishment of STAT5 phosphorylation. Specific inhibition of the "analog-sensitive" mutant AS-Jak1 but not AS-Jak3 by the ATP-competitive analog 1NM-PP1 abrogated IL-2 signaling, corroborating the data with the selective Jak3 inhibitor. Jak1 thus plays a dominant role over Jak3 and these data challenge the notion that selective ATP-competitive Jak3 kinase inhibitors will be effective.     

Molecular recognition of endocrine disruptors by synthetic and natural 17β-estradiol receptors: a comparative study

A β-estradiol receptor binding mimic was synthesised using molecular imprinting. Bulk polymers and spherical polymer nanoparticles based on methacrylic acid and ethylene glycol dimethacrylate as the functional monomer and crosslinker, respectively, were prepared in acetonitrile. The selectivity was evaluated by radioligand binding assays. The imprinted polymers were very specific to β-estradiol since the control polymers bound virtually none of the radioligand. The bulk polymer was then employed to screen endocrine disrupting chemicals. Structurally related steroids like α-estradiol, estrone and ethynylestradiol showed, respectively, 14.0, 5.0 and 0.7% of relative binding to the β-estradiol polymer, whereas most unrelated chemicals did not bind at all. These results are compared to those obtained with a bioassay using stably transfected yeast cells in culture bearing the human estrogen receptor. The receptor was activated by several estrogen-like chemicals and to a lesser extent by some structurally related chemicals. Figure A molecularly imprinted polymer that was a synthetic receptor for beta-estradiol was used for the screening of endocrine disrupting chemicals that are structurally related or unrelated to beta-estradiol. The results were compared with the recognition of the compounds by the biological estrogen receptor expressed in yeast cells. Related steroids like alpha-estradiol, estrone and ethynylestradiol showed significant binding to the beta-estradiol imprinted polymer, whereas most unrelated chemicals did not bind. The biological receptor was activated by several estrogen-like chemicals, and to a lesser extent by some structurally related chemicals     

How does a reversible electrode respond in a.c. voltammetry? Part 2: solutions for the periodic current amplitudes

Journal of Solid State Electrochemistry - In a.c. voltammetry, a programmed electrical potential—a linear ramp modulated by a sine wave of frequency ω and modest amplitude—is...     

Synthesis of a unique dimethyl thiazoline containing intermediate of novel peroxisome proliferator-activated receptors(PPAR)δ agonists

Peroxisome proliferator-activated receptor delta (PPARδ) is considered as a promising biological target for the development of new drugs to treat metabolic syndrome including hyperlipidemia. In this study, a simple and efficient method for the preparation of a unique dimethyl thiazoline containing intermediate (13) of new PPARδ agonists as GW501516 analogue is described. The intermediate 13 was readily obtained by coupling reaction of 4-(chloromethyl)-5,5-dimethyl-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrothiazole (11) with 4-mercapto-2-methylphenol (12) in the presence of tetrabutylammonium hydrogensulfate (TBAHS) and Cs₂CO₃ in DMF at 80?°C for 1?h. This unique intermediate could be useful for the synthesis of various novel PPARδ agonists to understand the structural and biological significance of PPARδ.     

N-glycosides. 9. Reaction of 3,5-O-isopropylidenexylofuranosylamine with β-isothiocyanatoaldehydes. Synthesis of new cyclonucleosides with a hexahydropyrimidine aglycone

The reaction of 3,5-O-isopropylidenexylofuranosylamine p-toluenesulfonate with -isothiocyanatoaldehydes in the presence of triethylamine gives 4,2-anhydro-4-hydroxy-3-(3,5-O-isopropylidene--D-xylofuranosyl)hexahydropyrimidine-2-thiones. The structure of these compounds and their deblocking products was studied by IR, UV, PMR, and ORD spectroscopy and mass spectrometry.For Communication 8, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1252–1258, September, 1993.     

Pterisemipol, a novel sesquiterpenoid from Pteris semipinnata L.

A novel sesquiterpenoid,pterisemipol,was isolated from Pteris semipinnata L.Its skeleton,namely pterisane,was considered to be rearranged from protoilludane and its structure was elucidated on the basis of spectroscopic analysis.     

Nanosensing of Fcγ receptors on macrophages

Determining the distribution of specific binding sites on biological samples with high spatial accuracy (in the order of several nanometer) is an important challenge in many fields of biological science. Combination of high-resolution atomic force microscope (AFM) topography imaging with single-molecule force spectroscopy provides a unique possibility for the detection of specific molecular recognition events. The identification and localization of specific receptor binding sites on complex heterogeneous biosurfaces such as cells and membranes are of particular interest in this context. Simultaneous topography and recognition imaging was used to unravel the nanolandscape of cells of the immune system such as macrophages. The most studied phagocytic receptors include the Fc receptors that bind to the Fc portion of immunoglobulins. Here, nanomapping of FcγRs (Fc receptors for immunoglobulin G (IgG)) was performed on fixed J774.A1 mouse macrophage cell surfaces with magnetically coated AFM tips functionalized with Fc fragments of mouse IgG via long and flexible poly(ethylene glycol) linkers. Because of possible AFM tip engulfment on living macrophages, appropriate cell fixation procedure leaving the binding activity of FcγRs practically intact was elaborated. The recognition maps revealed prominent spots (microdomains) more or less homogeneously distributed on the macrophage surface with the sizes from 4 to 300 nm. Typical recognition image contained about ∼4% of large clusters (>200 nm), which were surrounded by a massive number (∼50%) of small-size (4–30 nm) and the rest by middle-size (50, 150 nm) domains. These spots were detected from the decrease of oscillation amplitude during specific binding between Fc-coated tip and FcγRs on macrophage surfaces. In addition, the effect of osmotic swelling on the topographical landscape of macrophage surfaces and on the reorganization of FcγRs was investigated.     

When Is a Bond Broken? The Polarizability Perspective.

The question of when a chemical bond can be said to be broken is of fundamental chemical interest but has not been widely studied. Herein we propose that the maxima of static polarizability along bond dissociation coordinates naturally define cutoff points for bond rupture, as they represent the onset of localization of shared electron density into constituent fragments. Examples of computed polarizability maxima over the course of bond cleavage in main-group and transition metal compounds are provided, across covalent, dative and charge-shift bonds. The behavior along reaction paths is also considered. Overall, the static polarizability is found to be a sensitive reporter of electronic structure reorganization associated with bond stretching, and thus can serve as a metric for describing bond cleavage (or diagnose the absence of a chemical bond).