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Natural Ligand (natural + ligand)
Selected AbstractsFunctional reconstitution of the HIV receptors CCR5 and CD4 in liposomesFEBS JOURNAL, Issue 21 2002François Devesa Reconstitution of membrane proteins allows their study in a membrane environment that can be manipulated at will. Because membrane proteins have diverse biophysical properties, reconstitution methods have so far been developed for individual proteins on an ad hoc basis. We developed a postinsertion reconstitution method for CCR5, a G protein coupled receptor, with seven transmembrane ,,helices and small ecto- and endodomains. A His6 -tagged version of CCR5 was expressed in mammalian cells, purified using the detergent N -dodecyl-,- d -maltoside (DDM) and reconstituted into preformed liposomal membranes saturated with DDM, removing the detergent with hydrophobic polystyrene beads. We then attempted to incorporate CD4, a protein with a single transmembrane helix and a large hydrophilic ectodomain into liposomal membranes, together with CCR5. Surprisingly, reconstitution of this protein was also achieved by the method. Both proteins were found to be present together in individual liposomes. The reconstituted CCR5 was recognized by several monoclonal antibodies, recognized its natural ligand, and CD4 bound a soluble form of gp120, a subunit of the HIV fusion protein that uses CD4 as a receptor. Moreover, cells expressing the entire fusion protein of HIV bound to the liposomes, indicating that the proteins were intact and that most of them were oriented right side out. Thus, functional coreconstitution of two widely different proteins can be achieved by this method, suggesting that it might be useful for other proteins. [source] Prostaglandin D2 pathway and peroxisome proliferator-activated receptor ,-1 expression are induced by mechanical loading in an osteoblastic cell lineJOURNAL OF PERIODONTAL RESEARCH, Issue 2 2006Chitpol Siddhivarn Objective:, The hypothesis underlying the current study was that the arachidonic acid cascade, specifically activation of the prostaglandin (PG) D2 pathway in osteoblasts, is an anabolic signal induced by mechanical loading. Background:, Previous studies have shown that mechanical loading of osteoblasts triggers cyclooxygenase (COX)-2, PGE2 and prostacyclin (PGI2) synthesis. Since modest mechanical loading of osteoblasts promotes bone formation, we sought to determine whether mechanical stress activates the osteoblastic PGD2 pathway resulting in the synthesis of osteogenic cyclopentenones, including ,12PGJ2. Methods:, Osteoblast monolayers were stretched using a Bioflex apparatus at a frequency of 1 Hz with 1% elongation. Cells and cell media were collected at various time points: 5, 10, 15, 30 min; and 1, 4, 16, 24 h. RNA was extracted for quantitative reverse transcriptase,polymerase chain reaction (RT,PCR). In certain experiments, cells were pre-labeled with 14C arachidonic acid prior to stretching. Radiolabeled metabolites in cell media were identified by reverse-phase high performance liquid chromatography (RP-HPLC). Osteoblasts were evaluated for an induction in bone nodule formation by stretching. Results:, Mechanical strain significantly increased mRNA expression of COX-1, COX-2, PGD2 synthase and peroxisome proliferator-activated receptor (PPAR) ,-1, but not of PPAR,-2 as compared to control unstretched cells (p < 0.05). Mechanical loading stimulated the release of PGE2, PGD2 and the PGD2 metabolite ,12PGJ2. Mechanical strain resulted in the induction of bone nodules. Conclusions:, This report indicates that mechanical loading of osteoblasts results in activation of PGD2 and the concomitant expression of transcription factor PPAR,-1 mRNA. The coordinated synthesis of ,12PGJ2, a natural ligand for PPAR,-1, with the increased expression of PPAR,-1, suggests that biomechanical transduction pathways that initially involve the activation of cyclooxygenases may also involve the activation of the ,12PGJ2,PPAR pathway. [source] FPRL-1 induces modifications of migration-associated proteins in human neutrophilsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 17 2006Karsten Boldt Abstract Human polymorphonuclear neutrophils (PMNs) are an important cell population of the innate immune system, which migrates following concentration gradients of chemokines or chemoattractants to locations of infection and inflammation in order to eliminate invading microorganisms and cell debris. For both migration and adhesion of PMNs to various tissues, the dynamic remodeling of the cytoskeleton is key prerequisite. In this context, the formyl peptide receptor-like,1 (FPRL-1) is an important chemoattractant receptor expressed on PMNs. In this study, we show that a short stimulation of FPRL-1 with either a synthetic peptide ligand (W-peptide) or a natural ligand (sCK,8-1) changes the protein pattern of PMNs as assessed by 2-D-DIGE. MS analysis of selected deregulated protein species resulted in the identification of proteins that are involved in the remodeling process of the actin- and tubulin-based cytoskeleton, such as L -plastin, moesin, cofilin, and stathmin. Subsequent validation experiments performed either by Western blotting or phosphoprotein-specific gel staining (Pro-Q Diamond) revealed that L -plastin is phosphorylated, whereas moesin, cofilin, and stathmin are dephosphorylated in PMNs upon FPRL-1 stimulation. These findings suggest that FPRL-1 signaling targets proteins that regulate the motility of PMNs and moreover show that 2-D-DIGE is a technique capable of detecting and quantifying differently modified (e.g., phosphorylated) protein variants. [source] Rapid induction of peroxisome proliferator,activated receptor , expression in human monocytes by monosodium urate monohydrate crystalsARTHRITIS & RHEUMATISM, Issue 1 2003Tohru Akahoshi Objective Peroxisome proliferator,activated receptor , (PPAR,) is a member of the nuclear hormone receptor superfamily and functions as a key regulator of lipid and glucose metabolism, atherosclerosis, and inflammatory responses. This study was undertaken to evaluate the biologic role of PPAR, in self-limiting episodes of acute gouty arthritis. To do this, we investigated PPAR, expression by monosodium urate monohydrate (MSU) crystal,stimulated monocytes, and we studied the effects of PPAR, ligands on crystal-induced acute inflammation. Methods PPAR, expression by MSU crystal,stimulated human peripheral blood mononuclear cells was determined by reverse transcription,polymerase chain reaction and immunostaining. Expression of CD36 on monocytes was detected by flow cytometric analysis. The effects of PPAR, ligands on in vitro crystal-induced cytokine production and on in vivo cellular infiltration during crystal-induced acute inflammation were also investigated. Results MSU crystals rapidly and selectively induced PPAR, expression by monocytes. Gene expression was detected as early as 2 hours, and maximum expression was observed at 4 hours after stimulation. The induced PPAR, was functional, since a PPAR, ligand was able to up-regulate CD36 expression on monocytes. A natural ligand of PPAR,, 15-deoxy-,12,14 -prostaglandin J2 (15deoxy-PGJ2), significantly reduced the crystal-induced production of cytokines by monocytes. Indomethacin inhibited cytokine production only at high concentrations, and an antidiabetic thiazolidinedione (troglitazone) failed to exert significant effects. Administration of troglitazone and 15deoxy-PGJ2 significantly prevented cellular accumulation in a mouse air-pouch model of MSU crystal,induced acute inflammation. Conclusion Rapid induction of PPAR, expression on monocytes by MSU crystals may contribute, at least in part, to the spontaneous resolution of acute attacks of gout. [source] Purification and crystallization of the human RXR, ligand-binding domain,9- cisRA complexACTA CRYSTALLOGRAPHICA SECTION D, Issue 3 2001Pascal F. Egea The purification and crystallization of the stoichiometric complex of human RXR, ligand-binding domain (hRXR, LBD) bound to its natural ligand 9- cis retinoic acid (9- cisRA) are described. A three-step purification yields a pure and homogenous complex. Based on the crystallization conditions of several other nuclear receptors, an exhaustive crystallization screening using carboxylic acids as precipitating agents was performed in association with the use of polyhydric alcohols acting as cosmotropic solutes. Crystals of the hRXR, LBD,9- cisRA complex grew in a tripartite mixture containing sodium formate, glycerol and propane-1,2-diol. Micro- and macroseeding were necessary to improve both the size and the quality of crystals in order to make them suitable for structure determination. [source] Physiological roles of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligandBIOFACTORS, Issue 1 2009Takayuki Sugiura Abstract 2-Arachidonoylglycerol is an arachidonic acid-containing monoacylglycerol isolated from the rat brain and canine gut as an endogenous ligand for the cannabinoid receptors (CB1 and CB2). 2-Arachidonoylglycerol binds to both the CB1 receptor, abundantly expressed in the nervous system, and the CB2 receptor, mainly expressed in the immune system, with high affinity, and exhibits a variety of cannabimimetic activities. Notably, anandamide, another endogenous ligand for the cannabinoid receptors, acts as a partial agonist at these cannabinoid receptors, whereas 2-arachidonoylglycerol acts as a full agonist. The results of structure-activity relationship experiments strongly suggested that 2-arachidonoylglycerol rather than anandamide is the true natural ligand for both the CB1 and the CB2 receptors. Evidence is gradually accumulating which shows that 2-arachidonoylglycerol plays physiologically and pathophysiologically essential roles in various mammalian tissues and cells. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source] Effects of 1,,25-dihydroxyvitamin D3 on transporters and enzymes of the rat intestine and kidney in vivoBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2010Edwin C. Y. Chow Abstract 1,,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the natural ligand of the vitamin D receptor (VDR), was found to regulate bile acid related transporters and enzymes directly and indirectly in the rat intestine and liver in vivo. The kidney is another VDR-rich target organ in which VDR regulation on xenobiotic transporters and enzymes is ill-defined. Hence, changes in protein and mRNA expression of nuclear receptors, transporters and enzymes of the rat intestine and kidney in response to 1,25(OH)2D3 treatment (0 to 2.56,nmol/kg/day intraperitoneally in corn oil for 4 days) were studied. In the intestine, protein and not mRNA levels of Mrp2, Mrp3, Mrp4 and PepT1 in the duodenum and proximal jejunum were induced, whereas Oat1 and Oat3 mRNA were decreased in the ileum after 1,25(OH)2D3 treatment. In the kidney, VDR, Cyp24, Asbt and Mdr1a mRNA and protein expression increased significantly (2- to 20-fold) in 1,25(OH)2D3 -treated rats, and a 28-fold increase of Cyp3a9 mRNA but not of total Cy3a protein nor Cyp3a1 and Cyp3a2 mRNA was observed, implicating that VDR played a significant, renal-specific role in Cyp3a9 induction. Additionally, renal mRNA levels of PepT1, Oat1, Oat3, Ost,, and Mrp4, and protein levels of PepT1 and Oat1 were decreased in a dose-dependent manner, and the ,50% concomitant reduction in FXR, SHP, HNF-1, and HNF-4, mRNA expression suggests the possibility of cross-talk among the nuclear receptors. It is concluded that the effects of 1,25(OH)2D3 changes are tissue-specific, differing between the intestine and kidney which are VDR-rich organs. Copyright © 2009 John Wiley & Sons, Ltd. [source] Potent Fluoro-oligosaccharide Probes of Adhesion in ToxoplasmosisCHEMBIOCHEM, Issue 15 2009Sarah A. Allman Abstract Unnatural, NMR- and MRI-active fluorinated sugar probes, designed and synthesised to bind to the pathogenic protein TgMIC1 from Toxoplasma gondii, were found to display binding potency equal to and above that of the natural ligand. Dissection of the binding mechanism and modes, including the first X-ray crystal structures of a fluoro-oligosaccharide bound to a lectin, demonstrate that it is possible to create effective fluorinated probe ligands for the study of, and perhaps intervention in, sugar,protein binding events. [source] Consistent Bioactive Conformation of the Neu5Ac,(2,3)Gal Epitope Upon Lectin BindingCHEMBIOCHEM, Issue 18 2008Anirban Bhunia Dr. Get to NOE MAG: Partial structures of GQ1b,, the natural ligand of the myelin-associated glycoprotein (MAG), have been synthesized and subjected to NOE experiments to determine their bioactive conformations. The experiments show that the flexible ,(2,3)-glycosidic linkage between N -acetylneuraminic acid and galactose present in all ligands adopts a "sialyl Lewisx -type" binding mode. This information is valuable for the future design of conformationally preorganized MAG inhibitors. [source] Structure-Based Discovery and Experimental Verification of Novel AI-2 Quorum Sensing Inhibitors against Vibrio harveyiCHEMMEDCHEM, Issue 8 2008Minyong Li Dr. Abstract Quorum sensing has been implicated in the control of pathologically relevant bacterial behavior such as secretion of virulence factors, biofilm formation, sporulation, and swarming motility. The AI-2 quorum sensing pathway is found in both Gram-positive and Gram-negative bacteria. Therefore, antagonizing AI-2 quorum sensing is a possible approach to modifying bacterial behaviour. However, efforts in developing inhibitors of AI-2-mediated quorum sensing are especially lacking. High-throughput virtual screening using the V.,harveyi LuxP crystal structure identified two compounds that were found to antagonize AI-2-mediated quorum sensing in V.,harveyi without cytotoxicity. The sulfone functionality of these inhibitors was identified as critical to their ability to mimic the natural ligand in their interactions with Arg,215 and Arg,310 of the active site. [source] Ghrelin: more than a natural GH secretagogue and/or an orexigenic factorCLINICAL ENDOCRINOLOGY, Issue 1 2005E. Ghigo Summary Ghrelin, an acylated peptide produced predominantly by the stomach, has been discovered to be a natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a). Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also nonendocrine actions that are explained by the widespread distribution of ghrelin and GHS-R expression. The likely existence of GHS-R subtypes and evidence that the neuroendocrine actions, but not all the other actions, of ghrelin depend on its acylation in serine-3 revealed a system whose complexity had not been completely explored by studying synthetic GHS. Ghrelin secretion is mainly regulated by metabolic signals and, in turn, the modulatory action of ghrelin on the control of food intake and energy metabolism seems to be among its most important biological actions. However, according to a recent study, ghrelin-null mice are neither anorectics nor dwarfs and this evidence clearly depicts a remarkable difference from leptin null mice. Nevertheless, the original and fascinating story of ghrelin, as well as its potential pathophysiological implications in endocrinology and internal medicine, is not definitively cancelled by these data as GHS-R1a null aged mice show significant alterations in body composition and growth, in glucose metabolism, cardiac function and contextual memory. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, there are several open questions awaiting an answer. How many ghrelin receptor subtypes exist? Is ghrelin ,the' or just ,a' GHS-R ligand? That is, are there other natural GHS-R ligands? Is there a functional balance between acylated and unacylated ghrelin forms, potentially with different actions? Within the next few years suitable answers to these questions will probably be found, making it possible to gain a better knowledge of ghrelin's potential clinical perspectives. [source] Endocrine responses to ghrelin in adult patients with isolated childhood-onset growth hormone deficiencyCLINICAL ENDOCRINOLOGY, Issue 6 2002Gianluca Aimaretti Summary objective Ghrelin, a 28 amino acid acylated peptide, is a natural ligand of the GH secretagogues (GHS) receptor (GHS-R), which is specific for synthetic GHS. Similar to synthetic GHS, ghrelin strongly stimulates GH secretion but also displays significant stimulatory effects on lactotroph and corticotroph secretion. It has been hypothesized that isolated GH deficiency (GHD) could reflect hypothalamic impairment that would theoretically involve defect in ghrelin activity. patients In the present study, we verified the effects of ghrelin (1 µg/kg i.v.) on GH, PRL, ACTH and cortisol levels in adult patients with isolated severe GHD [five males and one female, age (mean ± SEM) 24·7 ± 2·6 years, BMI 25·7 ± 2·7 kg/m2]. In all patients, the GH response to insulin-induced hypoglycaemia (ITT, 0·1 IU regular insulin i.v.) and GH releasing hormone (GHRH) (1 µg/kg i.v.) + arginine (ARG, 0·5 g/kg i.v.) was also studied. The hormonal responses in GHD were compared with those in age-matched normal subjects (NS, seven males, age 28·6 ± 2·9 years, BMI 22·1 ± 0·8 kg/m2). results IGF-I levels in GHD were markedly lower than in NS (69·8 ± 11·3 vs. 167·9 ± 19·2 µg/l, P < 0·003). Ghrelin administration induced significant increase in GH, PRL, ACTH and cortisol levels in all GHD. In GHD, the GH response to ghrelin was higher (P < 0·05) than that to GHRH + ARG, which, in turn, was higher (P < 0·05) than that to ITT (9·2 ± 4·1 vs. 5·3 ± 1·7 vs. 1·4 ± 0·4 µg/l). These GH (1 µg/l = 2 mU/l) responses in GHD were markedly lower (P < 0·0001) than those in NS (ghrelin vs. GHRH + ARG vs. ITT 92·1 ± 16·7 vs. 65·3 ± 8·9 vs. 17·7 ± 3·5 µg/l). In GHD, the highest individual peak GH response to ghrelin was markedly lower than the lowest peak GH response in NS (28·5 vs. 42·9 µg/l). GHD and NS showed overlapping PRL (1 µg/l = 32 mU/l) (10·0 ± 1·4 vs. 14·9 ± 2·2 µg/l), ACTH (22·3 ± 5·3 vs. 18·7 ± 4·6 pmol/l) and cortisol responses (598·1 ± 52·4 vs. 486·9 ± 38·9 nmol/l). conclusions This study shows that ghrelin is one of the most powerful provocative stimuli of GH secretion, even in those patients with isolated severe GHD. In this condition, however, the somatotroph response is markedly reduced while the lactotroph and corticotroph responsiveness to ghrelin is fully preserved, indicating that this endocrine activity is fully independent of mechanisms underlying the GH-releasing effect. These results do not support the hypothesis that ghrelin deficiency is a major cause of isolated GH deficiency but suggest that ghrelin might represent a reliable provocative test to evaluate the maximal GH secretory capacity provided that appropriate cut-off limits are assumed. [source] Interaction between catalytically inactive calpain and calpastatinFEBS JOURNAL, Issue 8 2006Evidence for its occurrence in stimulated cells Conformational changes in the calpain molecule following interaction with natural ligands can be monitored by the binding of a specific monoclonal antibody directed against the catalytic domain of the protease. None of these conformational states showed catalytic activity and probably represent intermediate forms preceding the active enzyme state. In its native inactive conformation, calpain shows very low affinity for this monoclonal antibody, whereas, on binding to the ligands Ca2+, substrate or calpastatin, the affinity increases up to 10-fold, with calpastatin being the most effective. This methodology was also used to show that calpain undergoes similar conformational changes in intact cells exposed to stimuli that induce either a rise in intracellular [Ca2+] or extensive diffusion of calpastatin into the cytosol without affecting Ca2+ homeostasis. The fact that the changes in the calpain state are also observed under the latter conditions indicates that calpastatin availability in the cytosol is the triggering event for calpain,calpastatin interaction, which is presumably involved in the control of the extent of calpain activation through translocation to specific sites of action. [source] Bioinformatics-based discovery and identification of new biologically active peptides for GPCR deorphanization,JOURNAL OF PEPTIDE SCIENCE, Issue 9 2007Jean Colette Abstract Owing to their involvement in many physiological and pathological processes, G-protein-coupled receptors (GPCRs) are interesting targets for drug development. Approximately, 100 endoGPCRs lack their natural ligands and remain orphan (oGPCRs). Consequently, oGPCR deorphanization appears a promising research field for the development of new therapeutics. On the basis of the knowledge of currently known GPCR/ligand couples, some oGPCRs may be targeted by peptides. However, to find new drugs for GPCRs, Genepep has developed a dedicated bioinformatics platform to screen transcriptomic databases for the prediction of new GPCR ligands. The peptide lists generated include specific data, such as chemical and physical properties, the occurrence of post-translational modifications (PTMs) and an annotation referring to the location and expression level of the related putative genes. This information system allows a selection through series of biological criteria of ,10 000 natural peptides including already known GPCR ligands and potential new candidates for GPCR deorphanization. The most promising peptides for functional assay screening and future development as therapeutic agents are under evaluation. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [source] Alcohol Suppresses IL-2,Induced CC Chemokine Production by Natural Killer CellsALCOHOLISM, Issue 9 2005Ting Zhang Background: Natural killer (NK) cells are a critical component of the host innate immune system. We investigated whether alcohol impairs NK cell function, particularly production of CC chemokines induced by interleukin (IL)-2, the natural ligands for CCR5 receptor. Methods: Primary NK cells and NK cell line (YTS) were cultured with or without alcohol (10 to 80 mM) for three hours. The culture supernatants were then harvested and used to treat human peripheral blood monocyte-derived macrophages and a HeLa cell line, which expresses CD4, CCR5, and CXCR4 receptors (MAGI cells). CC chemokine expression by YTS and primary NK cells treated with or without alcohol was analyzed with the real-time RT-PCR and ELISA. Ca2+i and Western blot assays were used to determine calcium-mediated intracellular signaling pathway and NF-,B p65 expression. HIV strains (Bal and UG024) were used to infect macrophages and MAGI cells. In addition, ADA (macrophage-tropic strain) and murine leukemia virus (MLV) envelope-pseudotyped HIV infection was carried out in macrophages. HIV infectivity was determined by HIV reverse transcriptase (RT) and ,-galactosidase activity assays. Results: Alcohol inhibited IL-2,induced CC chemokine (CCL3 and CCL4) expression by NK cells. Functional tests demonstrated that this reduced expression of CC chemokines was associated with diminished anti-HIV ability of NK cells. Alcohol also reduced the ability of NK cells to response to CCL3-mediated chemotaxis. Alcohol inhibited IL-2,induced NF-,B p65 protein expression and calcium mobilization by NK cells. Conclusions: Alcohol, through the inhibition of IL-2,induced NF-,B p65 protein expression and intracellular calcium mobilization, suppressed NK cell production of CC chemokines. This suppression of CC chemokine production was associated with diminished anti-HIV activity of NK cells. Thus, by inhibiting NK cell,mediated innate immunity against HIV, alcohol consumption may have a cofactor role in the immunopathogenesis of HIV disease. [source] TRP channels as therapeutic targets: hot property, or time to cool down?NEUROGASTROENTEROLOGY & MOTILITY, Issue 8 2006G. A. Hicks Abstract,Transient receptor potential (TRP) channels are involved in a wide range of processes ranging from osmoregulation, thermal, chemical and sensory signalling, and potentially in the pathophysiology associated with several diseases. Patents for TRPV1 antagonists alone span diseases ranging across chronic pain, neuropathies, headache, bladder disorders, irritable bowel syndrome (IBS), gastro-oesophageal reflux disease (GORD), and cough amongst others. Most research is currently focused around those TRP channels involved in sensory processes, with the neurogastroenterology and motility field playing a major role, for example, through recent discoveries of differential roles for TRPV receptor subtypes in chemosensitivity and mechanosensitivity of visceral afferents. At this time, however, the understanding of the role of even TRPV1, let alone most of the other TRP channels in disease pathophysiology is only just beginning, and although enthusiasm around the therapeutic potential for modulators of these channels is understandable, based largely upon the experience of the effects of natural ligands, such as capsaicin, the sheer size and complexity of the TRP family as a whole must serve as a warning against expecting too much too soon from drug discovery efforts. [source] Analysis of the HLA class I associated peptide repertoire in a hepatocellular carcinoma cell line reveals tumor-specific peptides as putative targets for immunotherapyPROTEOMICS - CLINICAL APPLICATIONS, Issue 3 2007Iñaki Alvarez Abstract HLA class I molecules present peptides on the cell surface to CD8+ T cells. The repertoire of peptides that associate to class I molecules represents the cellular proteome. Therefore, cells expressing different proteomes could generate different class I-associated peptide repertoires. A large number of peptides have been sequenced from HLA class I alleles, mostly from lymphoid cells. On the other hand, T cell immunotherapy is a goal in the fight against cancer, but the identification of T cell epitopes is a laborious task. Proteomic techniques allow the definition of putative T cell epitopes by the identification of HLA natural ligands in tumor cells. In this study, we have compared the HLA class I-associated peptide repertoire from the hepatocellular carcinoma (HCC) cell line SK-Hep-1 with that previously described from lymphoid cells. The analysis of the peptide pool confirmed that, as expected, the peptides from SK-Hep-1 derive from proteins localized in the same compartments as in lymphoid cells. Within this pool, we have identified 12 HLA class I peptides derived from HCC-related proteins. This confirms that tumor cell lines could be a good source of tumor associated antigens to be used, together with MS, to define putative epitopes for cytotoxic T cells from cancer patients. [source] Nuclear magnetic resonance studies of CXC chemokine receptor 4 allosteric peptide agonists in solutionCHEMICAL BIOLOGY & DRUG DESIGN, Issue 2005O.K. Baryshnikova Abstract:, CXC chemokine receptor 4 (CXCR4) is an important pharmacological target due to its involvement in HIV-1 pathogenesis and cancer metastasis. Two recently discovered allosteric agonists that bind and activate CXCR4, the ASLW and RSVM peptides, were analyzed using solution nuclear magnetic resonance spectroscopy. Both peptides assumed an extended backbone conformation with several well-defined local motifs in the regions from residues 5 to 8 and 9 to 12. The local structures in the region of residues 5,8 were different for agonists studied here and natural ligands. The local structure in the region 9,12 was adopted by the entire ensemble of the ASLW peptide structures and by the subset of conformations for the RSVM peptide. The same turn was found in full-length stromal derived factor (SDF)-1 and in the small family of the SDF-1 N-terminal 17-mer. Similar examples in literature suggest the relevance of nascent structures in peptides to their biologically relevant conformations. The significance of found local structures and implications for further drug design are discussed. [source] Structure of the Glucocorticoid Receptor, a Flexible Protein That Can Adapt to Different LigandsCHEMMEDCHEM, Issue 5 2010Adriana Crystal structures of the glucocorticoid receptor (GR) ligand binding domain in complex with various agonists and antagonists give us an insight on how ligands are recognized by the receptor and how their structure can affect the behavior of the GR. Interestingly, these structural data show how the GR can adapt its binding pocket to accommodate molecules that differ substantially from the natural ligands without loss of function. [source] | ||||||||||||||||