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Receptor Binding Sites (receptor + binding_site)
Selected AbstractsPhoto-CIDNP Study of the Interaction of Tyrosine with Nifedipine.PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 3 2004An Attempt to Model the Binding Between Calcium Receptor, Calcium Antagonist Nifedipine This article proposes a new approach to the modeling of the molecular-level mechanism of ligand-receptor interaction for Ca2+ receptor binding site. Chemically induced dynamic nuclear polarization (CIDNP) technique has been used to unravel fine details of the reaction in the model system composed of one of the known Ca2+ antagonist drugs, nifedipine (NF), and isolated amino acid residuals (e.g. tyrosine [Tyr]) of Ca2+ receptor binding site. It has been conclusively demonstrated that the reaction between NF and Tyr resulting in the oxidation product,nitroso form of NF,obeys the radical mechanism. CIDNP data in combination with the results of mathematical modeling of the structures of ligandreceptor complexes have allowed to propose the mechanism of the interaction of NF with Ca2+ receptor binding site. [source] Determination of the human type I interferon receptor binding site on human interferon-,2 by cross saturation and an NMR-based model of the complexPROTEIN SCIENCE, Issue 11 2006Sabine R. Quadt-Akabayov Abstract Type I interferons (IFNs) are a family of homologous helical cytokines that exhibit pleiotropic effects on a wide variety of cell types, including antiviral activity and antibacterial, antiprozoal, immunomodulatory, and cell growth regulatory functions. Consequently, IFNs are the human proteins most widely used in the treatment of several kinds of cancer, hepatitis C, and multiple sclerosis. All type I IFNs bind to a cell surface receptor consisting of two subunits, IFNAR1 and IFNAR2, associating upon binding of interferon. The structure of the extracellular domain of IFNAR2 (R2-EC) was solved recently. Here we study the complex and the binding interface of IFN,2 with R2-EC using multidimensional NMR techniques. NMR shows that IFN,2 does not undergo significant structural changes upon binding to its receptor, suggesting a lock-and-key mechanism for binding. Cross saturation experiments were used to determine the receptor binding site upon IFN,2. The NMR data and previously published mutagenesis data were used to derive a docking model of the complex with an RMSD of 1 Å, and its well-defined orientation between IFN,2 and R2-EC and the structural quality greatly improve upon previously suggested models. The relative ligand,receptor orientation is believed to be important for interferon signaling and possibly one of the parameters that distinguish the different IFN I subtypes. This structural information provides important insight into interferon signaling processes and may allow improvement in the development of therapeutically used IFNs and IFN-like molecules. [source] Decapeptide with fibroblast growth factor (FGF)-5 partial sequence inhibits hair growth suppressing activity of FGF-5JOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2003Chikako Ito Earlier studies demonstrated that knock-out of fibroblast growth factor-5 gene (Fgf-5) prolonged anagen VI phase of hair cycle, resulting long hairs in the mice. We showed the activities on hair growth of the two Fgf-5 gene products, one of which, FGF-5 suppressed hair growth by inhibiting anagen proceeding and inducing the transition from anagen to catagen, and FGF-5S, a shorter polypeptide with FGF-5-antagonizing activity translated from alternatively spliced mRNA, suppressed this activity of FGF-5. As the results suggested that FGF-5 antagonist would increase hair growth, we synthesized various peptides having partial sequences of human FGF-5 and FGF-5S and determined their FGF-5 antagonist activity. Among them, a decapeptide designated P3 (95-VGIGFHLQIY-104) that aligns with receptor binding sites of FGF-1 and FGF-2 suppressed FGF-5-induced proliferation of BALB/3T3 A31 and NIH/3T3 murine fibroblasts, and FGF receptor-1c (FGFR-1c)-transfected Ba/F3 cell line (FR-Ba/F3 cells). IC50s of this peptide on these cell proliferations were 64, 28, 146 ,M, respectively. On the other hand, IC50 of this peptide on binding of FGF-5 to the FGFR-1(IIIc)/Fc chimera was 483 ,M. Examination in dorsal depilated mice revealed that the P3 peptide reduced the activity of FGF-5 to recover hair pigmentation and hair follicle lengths. The classification of histologically observed skin sections showed FGF-5-induced delations of anagen procedure had reduced by the P3 peptide. The anti-Ki67 antibody staining of hair follicles was inhibited by administration of FGF-5, and this inhibition by FGF-5 was recovered by administration of the P3 peptide. The P3 peptide alone did not affect hair follicle length and hair cell proliferation. These results indicate that the decapeptide antagonized FGF-5 activity in vivo, and reduced the inhibition of FGF-5 in hair growth, confirming that FGF-5 inhibitors are promising substances against hair loss and/or for promoting hair growth. J. Cell. Physiol. 197: 272,283, 2003. © 2003 Wiley-Liss, Inc. [source] 16 Kallikrein 15 (KLK15) in prostate cancer: in silico analysis and single nucleotide polymorphism verificationBJU INTERNATIONAL, Issue 2006M.A. KEDDA Introduction:, Prostate cancer is the most common cancer in Caucasian men and there is strong evidence that kallikreins are part of an enzymatic cascade pathway activated in this disease. Altered KLK15 expression has been associated with cancer progression and grade and we postulate that single nucleotide polymorphisms (SNPs) in the KLK15 gene, will alter gene expression and will be associated with prostate cancer susceptibility and prognosis. Materials and Methods:, We have used in silico prediction of function of wildtype and variant promoter sequences through assessment of hormone receptor elements and transcription factor binding sites; as well as prediction of likely splice variants through genomic, splicing and EST databases and web sites, and multiple sequence alignment packages. We have also used PCR and sequence analysis to further characterise the promoter region of the gene. Results:,In silico analysis of the KLK15 gene has identified the following: two putative promoter regions, two putative androgen response elements (AREs) and four putative estrogen response elements (EREs); two clusters of cis elements; and 109 SNPs. Forty-seven SNPs alter transcription factor sites (22 gain sites), 20 gain/increase probability of an ERE and three alter nuclear hormone receptor binding sites. Three new EST clones have been identified by analysis of gene expression in CGAP databases and suggest a new KLK15 splice variant, with a different start site. Conclusion:, We have identified a number of new SNPs in the KLK15 gene, which may be functionally important and, in collaboration with the Queensland Cancer Fund (ProsCan Study), we will further investigate the association of these SNPs with prostate cancer risk and prognosis. [source] Pharmacology and autoradiography of human DP prostanoid receptors using [3H]-BWA868C, a DP receptor-selective antagonist radioligandBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2000N A Sharif A potent and highly selective DP prostanoid receptor antagonist radioligand, [3H]-cyclohexyl-N-BWA868C (3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethyl-amino) hydantoin, ([3H]-BWA868C)), has been generated for receptor binding and autoradiographic studies. Specific [3H]-BWA868C binding to human platelet membranes achieved equilibrium within 60 min at 23°C and constituted up to 95% of the total binding. The association (K+1) and dissociation (K,1) rate constants of binding were 0.758±0.064 min,1, mmol and 0.0042±0.0002 min,1, respectively, yielding dissociation constants (KDs) of 5.66±0.44 nM (n=4). Specific [3H]-BWA868C bound to DP receptors with a high affinity (KD=1.45±0.01 nM, n=3) and to a finite, saturable number of binding sites (Bmax=21.1±0.6 nmol g,1 wet weight). DP receptor class prostanoids (e.g. ZK118182, BW245C, BWA868C, PGD2) exhibited high (nanomolar) affinities for [3H]-BWA868C binding, while prostanoids selective for EP, FP, IP and TP receptors showed a low (micromolar) affinity. Specific DP receptor binding sites were autoradiographically localized on the ciliary epithelium/process, longitudinal and circular ciliary muscles, retinal choroid and iris in human eye sections using [3H]-BWA868C. While [3H]-PGD2 yielded similar quantitative distribution of DP receptors as [3H]-BWA868C, the level of non-specific binding observed with [3H]-PGD2 was significantly greater than that observed with [3H]-BWA868C. It is concluded that [3H]-BWA868C is a high-affinity and very specific DP receptor radioligand capable of selectively labelling the DP receptor. [3H]-BWA868C may prove useful for future homogenate-based and autoradiographic studies on the DP receptor. British Journal of Pharmacology (2000) 131, 1025,1038; doi:10.1038/sj.bjp.0703686 [source] Binding characteristics of BmK I, an ,-like scorpion neurotoxic polypeptide, on cockroach nerve cord synaptosomesCHEMICAL BIOLOGY & DRUG DESIGN, Issue 4 2000Y.-J. Li Abstract: In this study, the binding characteristics of BmK I, an ,-like neurotoxic polypeptide purified from the venom of the Chinese scorpion Buthus martensi Karsch, were investigated on rat brain and cockroach nerve cord synaptosomes. The results showed that BmK I can bind to a single class of noninteracting binding sites on cockroach nerve cord synaptosomes with medium affinity (Kd = 16.5 ± 4.4 nm) and low binding capacity (Bmax= 1.05 ± 0.23 pmol/mg protein), but lacks specific binding on rat brain synaptosomes. BmK AS, BmK AS-1 (two novel sodium channel-blocking ligands), BmK IT (an excitatory insect-selective toxin) and BmK IT2 (a depressant insect-selective toxin) from the same venom were found to be capable of depressing BmK I binding in cockroach nerve cord synaptosomes, which might be attributed to either allosteric modulation of voltage-gated Na+ channels by these toxic polypeptides or partial overlapping between the receptor binding sites of BmK I and these toxins. This thus supported the notion that ,-like scorpion neurotoxic polypeptides bind to a distinct receptor site on sodium channels, which might be similar to the binding receptor site of ,-type insect toxins, and also related to those of BmK AS type and insect-selective scorpion toxins on insect sodium channels. [source] | |||||||||||||