Binding Selectivity (binding + selectivity)

Distribution by Scientific Domains


Selected Abstracts


Prediction of the Three-Dimensional Structure for the Rat Urotensin,II Receptor, and Comparison of the Antagonist Binding Sites and Binding Selectivity between Human and Rat Receptors from Atomistic Simulations

CHEMMEDCHEM, Issue 9 2010
Soo-Kyung Kim Dr.
Abstract Urotensin-II (U-II) has been shown to be the most potent mammalian vasoconstrictor known. Thus, a U-II antagonist might be of therapeutic value in a number of cardiovascular disorders. However, interspecies variability of several nonpeptidic ligands complicates the interpretation of in vivo studies of such antagonists in preclinical animal disease models. ACT058362 is a selective antagonist for the human U-II receptor (hUT2R) with a reported Kd value of ,4,nM in a molecular binding assay, but it is reported to bind weakly to rat UT2R (rUT2R), with a Kd value of ,1,500,nM. In contrast, the arylsulphonamide SB706375 is a selective antagonist against both hUT2R (Kd=,9,nM) and rUT2R (Kd=,21,nM). To understand the species selectivity of the UT2R, we investigated the binding site of ACT058362 and SB706375 in both hUT2R and rUT2R to explain the dramatically lower (,400-fold) affinity of ACT058362 for rUT2R and the similar affinity (,10,nM) of SB706375 for both UT2Rs. These studies used MembStruk and MSCDock to predict the UT2R structure and the binding site of ACT058362 and SB706375. Based on binding energies, we found two binding modes each with D1303.32 as the crucial anchoring point (Ballesteros,Weinstein numbering given in superscript). We predict that ACT058362 (an aryl,amine,aryl or ANA ligand) binds in the transmembrane (TM) 3456 region, while SB706375 (an aryl,aryl,amine or AAN ligand) binds in the TM 1237 region. These predicted sites explain the known differences in binding of the ANA ligand to rat and human receptors, while explaining the similar binding of the AAN compound to rat and human receptors. Moreover the predictions explain currently available structure,activity relationship (SAR) data. To further validate the predicted binding sites of these ligands in hUT2R and rUT2R, we propose several mutations that would help define the structural origins of differential responses between UT2R of different species, potentially indicating novel UT2R antagonists with cross-species high affinity. [source]


Toward the development of new medicinal leads with selectivity for protein kinase C isozymes

THE CHEMICAL RECORD, Issue 4 2005
Kazuhiro Irie
Abstract Tumor promoters such as phorbol esters bind strongly to protein kinase C (PKC) isozymes to induce their activation. Since each PKC isozyme is involved in diverse biological events in addition to tumor promotion, the isozymes serve as promising therapeutic targets. Tumor promoters bind to the C1A and/or C1B domain of conventional (,, ,I, ,II, and ,) and novel PKC isozymes (,, ,, ,, and ,). As these C1 domains play differential roles in PKC activation and their translocation in cells, the development of agents with binding selectivity for individual C1 domains is a pressing need. For this purpose, we established a synthetic C1 peptide library of all PKC isozymes. The library enabled us to identify indolactam-V (1) as a promising lead compound. Our diverse structure,activity studies on 1 indicated that the position of the hydrophobic substituent on the indole ring dominates the PKC isozyme- and C1 domain-selective binding rather than conformation of the nine-membered lactam. Moreover, we suggested that the indole ring of 1 could be involved in the CH/, interaction with Pro-11 of the C1B domain of PKC,. This invaluable information will lead to the structural optimization of the PKC, ligand as exemplified by the design and synthesis of naphtholactam-V8 (21). © 2005 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 5: 185,195; 2005: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20044 [source]


Efficient expression and purification of human aglycosylated Fc, receptors in Escherichia coli,

BIOTECHNOLOGY & BIOENGINEERING, Issue 1 2010
Sang Taek Jung
Abstract Effector Fc gamma receptors (Fc,Rs) are expressed on the surface of a variety of cells of hematopoietic lineage and serve as a bridge between adaptive and innate immune responses. The interaction between immune complexes, formed by IgG class antibodies that are crosslinked with antigen, and Fc,Rs triggers signaling cascades that result in numerous cellular responses including the activation or donwregulation of cytotoxic responses, cytokine release, and antibody synthesis. Here, the extracellular domains of the human type I transmembrane Fc,Rs were expressed in Escherichia coli and their interactions to subclass IgGs (IgG1, IgG2, IgG3, and IgG4) antibodies were analyzed. Expression using fully synthetic E. coli codon optimized Fc,R genes and optimization of sequences for N-terminal translation initiation region through mRNA secondary structure prediction enabled us to achieve high yield of purified, bacterially expressed receptors, including Fc,RI and Fc,RIIIa which have not been successfully expressed in bacteria until now. The aglycosylated Fc,Rs showed similar IgG subclass binding selectivity compared to the respective glycosylated Fc,Rs expressed in mammalian cells. Biotechnol. Bioeng. 2010;107: 21,30. © 2010 Wiley Periodicals, Inc. [source]


Influence of peptide ligand surface density and ethylene oxide spacer arm on the capture of porcine parvovirus

BIOTECHNOLOGY PROGRESS, Issue 5 2009
Caryn L. Heldt
Abstract In previous work, we identified two trimeric peptide ligands (designated WRW and KYY), which bound specifically to porcine parvovirus (PPV) and demonstrated their ability to capture and remove the virus from solutions containing 7.5% human blood plasma. This article examines the influences of peptide density and the presence of an ethylene oxide spacer arm on the efficiency of virus capture using these two ligands. The WRW peptide bound the most virus from plasma solutions at the lowest peptide density tested (0.008 mmol/g dry resin), and binding was enhanced by the presence of the spacer arm. On the other hand, the KYY peptide bound the most viruses at the same low peptide density, but it performed better in the absence of the spacer arm. Of the two, the binding efficiency of the WRW peptide was more sensitive to peptide density and spacer arm presence. These results indicate that low peptide densities enhance binding selectivity, facilitating specific peptide-virus binding even in the presence of plasma proteins which can theoretically bind nonspecifically. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009 [source]


Selective targeting of a laccase from Stachybotrys chartarum covalently linked to a carotenoid-binding peptide

CHEMICAL BIOLOGY & DRUG DESIGN, Issue 1 2004
G.G. Janssen
Abstract:, A two-step targeting strategy was used to identify improved laccases for bleaching carotenoid-containing stains on fabric. We first applied a modified phage display technique to identify peptide sequences capable of binding specifically to carotenoid stains and not to fabric. Prior deselection on the support on which the carotenoid was localized, increased stringency during the biopanning target selection process, and analysis of the phage peptides' binding to the target after acid elution and polymerase chain reaction (PCR) postacid elution, were used to isolate phage peptide libraries with increased binding selectivity and affinity. Peptide sequences were selected based on identified consensus motifs. We verified the enhanced carotenoid-binding properties of the peptide YGYLPSR and subsequently cloned and expressed C-terminal variants of laccase from Stachybotrys chartarum containing carotenoid-binding peptides YGYLPSR, IERSAPATAPPP, KASAPAL, CKASAPALC, and SLLNATK. These targeted peptide,laccase fusions demonstrate enhanced catalytic properties on stained fabrics. [source]


Protonated Macrobicyclic Hosts Containing Pyridine Head Units for Anion Recognition

CHEMISTRY - A EUROPEAN JOURNAL, Issue 19 2008
David Esteban-Gómez Dr.
Abstract In this paper, we report two macrobicyclic receptors containing pyridine head units derived from 1,10-diaza-15-crown[5] (L1) or 4,13-diaza-18-crown[6] (L2) that can be protonated in MeCN and used for anion recognition. The interaction of these protonated lateral macrobicycles with different anions has been investigated by means of spectrophotometric titrations in MeCN. The association constants for the complexes of halide anions with the protonated macrobicycles follow the sequences Cl,>Br,>I,>F, (L1) and Cl,>F,>I,>Br, (L2), whereby an increase of more than two logarithmic units is observed from F, to Cl, for the binding constants of the receptor derived from L1. The association constants also indicate an important degree of selectivity of these macrobicyclic receptors for Cl, over Br, or I,. The X-ray crystal structure analyses of the chloride and bromide complexes confirms the formation of the envisaged supramolecular complexes. Moreover, the binding constants indicate that these receptors present a high sulfate-to-nitrate binding selectivity. The stability trend observed for the recognition of halide anions by the macrobicycles presented herein as well as the sulfate-to-nitrate binding selectivity have been rationalised by means of DFT calculations at the B3LYP/LanL2DZ level. These studies indicate that the especially high binding selectivity for Cl, is the result of the optimum fit between the protonated macrobicyclic cavity and the size of the anion, whereas the sulfate-to-nitrate selectivity results from shape complementarity between the hydrogen-binding acceptor sites on sulfate and the hydrogen-bond donors of the macrobicycle. [source]