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1.
Conformation of neuropeptide Y receptor antagonists: structural implications in receptor selectivity
Two NPY analogue peptides, BVD10 (Ile-Asn-Pro-Ile-Tyr-Arg-Leu-Arg-Tyr-OMe) and BVD15 (Ile-Asn-Pro-Ile-Tyr-Arg-Leu-Arg-Tyr-NH(2)) were characterized conformationally by NMR, CD and molecular dynamics simulations. The two peptides exhibit different secondary structure characteristics in trifluoroethanol. BVD10 exhibits a structure with two consecutive beta-turns at Asn2-Pro3-Ile4-Tyr5 and Ile4-Tyr5-Arg6-Leu7. BVD15 exhibits a helical type of structure along with a beta-turn at Asn2-Pro3-Ile4-Tyr5. Molecular modeling studies suggested that the C-terminus Tyr9 is oriented in different directions in the two peptides. The difference in the structures of peptides observed may contribute to the Y(1) selectivity of BVD10 relative to BVD15. 相似文献
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Repeated administration of LSD to rats (100 μg/kg every 6 hours for 4 days) resulted in significant decreases in both the KD (?17 &; ?23%) and Bmax (?25 %&; ?30%) for [3H]—5HT binding in forebrain and brainstem plus spinal cord. [3H] — LSD binding showed significant changes in Bmax values (?19%) in forebrain and brainstem plus spinal cord, while KD values were not significantly changed. Neither a single injection of LSD (100 μg/kg) nor repeated administration of brom-LSD (100 μg/kg every 6 hours for 4 days) produced any significant changes in binding. In addition, repeated LSD administration produced no significant changes in [3H] — spiroperidol binding. 相似文献
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Ligand-specific receptor states: implications for opiate receptor signalling and regulation 总被引:1,自引:0,他引:1
Opiate drugs produce their effects by acting upon G protein coupled receptors (GPCRs) and although they are among the most effective analgesics available, their clinical use is restricted by unwanted side effects such as tolerance, physical dependence, respiratory depression, nausea and constipation. As a class, opiates share a common profile of unwanted effects but there are also significant differences in ligand liability for producing these actions. A growing number of studies show that GPCRs may exist in multiple active states that differ in their signalling and regulatory properties and which may distinctively bind different agonists. In this review we summarize evidence supporting the existence of multiple active conformations for MORs and DORs, analyze information favouring the existence of ligand-specific receptor states and assess how ligand-selective efficacy may contribute to the production of longer lasting, better tolerated opiate analgesics. 相似文献
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Protein disorder prediction: implications for structural proteomics 总被引:26,自引:0,他引:26
Linding R Jensen LJ Diella F Bork P Gibson TJ Russell RB 《Structure (London, England : 1993)》2003,11(11):1453-1459
A great challenge in the proteomics and structural genomics era is to predict protein structure and function, including identification of those proteins that are partially or wholly unstructured. Disordered regions in proteins often contain short linear peptide motifs (e.g., SH3 ligands and targeting signals) that are important for protein function. We present here DisEMBL, a computational tool for prediction of disordered/unstructured regions within a protein sequence. As no clear definition of disorder exists, we have developed parameters based on several alternative definitions and introduced a new one based on the concept of "hot loops," i.e., coils with high temperature factors. Avoiding potentially disordered segments in protein expression constructs can increase expression, foldability, and stability of the expressed protein. DisEMBL is thus useful for target selection and the design of constructs as needed for many biochemical studies, particularly structural biology and structural genomics projects. The tool is freely available via a web interface (http://dis.embl.de) and can be downloaded for use in large-scale studies. 相似文献
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A single gene codes for the nicotinic acetylcholine receptor alpha-subunit in Torpedo marmorata: structural and developmental implications. 总被引:3,自引:1,他引:2
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We have used Southern blot hybridization to analyze the genomic structure encoding the alpha-subunit of the acetylcholine receptor (AChR) in Torpedo marmorata, with cDNA probes isolated from the electric organ. Four different radiolabelled probes, corresponding to various parts of the alpha-subunit mRNA, hybridized to several genomic fragments of T. marmorata DNA generated by digestion with the restriction enzymes SstI, PvuII and PstI. The same hybridization pattern was observed after washing the blots under low- or high-stringency conditions. As a check for detection sensitivity of heterologous sequences, the same probes were hybridized to PvuII-digested chicken DNA, revealing bands at low stringency which disappeared at higher stringencies. Unambiguously, two of our probes (one of them entirely within the coding region) hybridized to a single genomic fragment from T. marmorata DNA. This feature, as well as the results of an extensive study of the whole hybridization pattern, points towards the uniqueness of alpha-subunit-specific sequences in the genome of T. marmorata. Since overall more bands were found than expected from the cDNA sequence, this alpha-subunit gene must be split by several introns (at least four, possibly more). The length of this gene is at least 20 kb. The existence of a single alpha-subunit gene is consistent with the absence of chemical heterogeneity in the NH2-terminal sequence of the purified alpha-chain, and supports the view that the two alpha-chains belonging to one AChR oligomer have an identical primary structure. It also suggests that localization and stabilization of the AChR in well-defined post-synaptic areas of T. marmorata electric organ basically relies, during development, on 'epigenetic' mechanisms. 相似文献
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MET meet adaptors: Functional and structural implications in downstream signalling mediated by the Met receptor 总被引:1,自引:0,他引:1
Bolanos-Garcia VM 《Molecular and cellular biochemistry》2005,276(1-2):149-157
The tyrosin kinase Met receptor regulates multiple cellular events, ranging from cell motility and angiogenesis to morphological differentiation and tissue regeneration. To conduce these activities, the cytoplasmic C-terminal region of this receptor acts as a docking site for multiple protein substrates, including Grb2, Gab1, STAT3, Shc, SHIP-1 and Src. These substrates are characterised by the presence of multiple domains, including the PH, PTB, SH2 and SH3 domains, which directly interact with the multisubstrate C-terminal region of Met. How this receptor recognises and binds a specific substrate in a space-temporal mode is a central question in cell signalling. The recently solved crystal structure of the tyrosine kinase domain of the Met receptor and that of domains of diverse Met substrates provides the molecular framework to understand Met substrate specificity. This structural information also gives new insights on the plasticity of Met signalling and the implications of Met deregulation in tumorigenic processes. In the light of these advances, the present work discusses the molecular basis of Met-substrate recognition and its functional implications in signalling events mediated by this pleiotropic receptor. (Mol Cell Biochem 276: 149–157, 2005) 相似文献
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Structural genomics is a broad initiative of various centers aiming to provide complete coverage of protein structure space. Because it is not feasible to experimentally determine the structures of all proteins, it is generally agreed that the only viable strategy to achieve such coverage is to carefully select specific proteins (targets), determine their structure experimentally, and then use comparative modeling techniques to model the rest. Here we suggest that structural genomics centers refine the structure-driven approach in target selection by adopting function-based criteria. We suggest targeting functionally divergent superfamilies within a given structural fold so that each function receives a structural characterization. We have developed a method to do so, and an itemized survey of several functionally rich folds shows that they are only partially functionally characterized. We call upon structural genomics centers to consider this approach and upon computational biologists to further develop function-based targeting methods. 相似文献
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Loci for human U1 RNA: structural and evolutionary implications 总被引:9,自引:0,他引:9
H J Monstein K Hammarstr?m G Westin J Zabielski L Philipson U Pettersson 《Journal of molecular biology》1983,167(2):245-257
Three clones U1-1, U1-6, and U1-8 containing sequences related to human U1 RNA have been studied by sequence analysis. The results show that each of the three clones represents a distinct locus. The U1-6 locus is closely related to the HU1-1 locus, which is believed to represent a functional U1 gene. The U1-1 and U1-8 loci are pseudogenes by definition, since they contain sequences that are closely related to but not identical with the human U1 RNA sequence. The U1-6 locus contains the sequence T-A-T-A-T close to the 5'-end of the U1 sequence but it is unclear if this represents the promoter. When the U1-8 locus was compared to the U1-6 locus, it was observed that the 5'-flanking sequences, except in the immediate vicinity of the pseudogene, are as well-conserved as the U1-related sequence itself, at least up to position -220. The high degree of homology in the 5'-flanking region suggests that U1 genes have a much more strict sequence requirement with regard to 5'-flanking sequences than most other eukaryotic genes. The U1-6 and U1-8 loci contain the sequence T-A-T-G-T-A-G-A-T-G-A between positions -211 and -221. An identical sequence is present in the equivalent position in the HU1-1 locus, and may represent the promoter. The high degree of conservation in the postulated promoter region indicates that pseudogenes like U1-8 possibly could be expressed. A truncated U1-related sequence is present between 106 to 150 nucleotides upstream from the U1 gene/pseudogene in the U1-6, the U1-8 and the HU1-1 loci, suggesting that the U1 genes may have been clustered early in evolution. The U1-1 locus has a strikingly different structure from the U1-8 locus; the pseudogene itself is as closely related to the U1 RNA sequence as is the U1-8 pseudogene but the flanking sequences, both on the 5' and the 3' side, share no detectable homology with the corresponding regions in the U1-6 or U1-8 loci. It may therefore be postulated that small nuclear RNA pseudogenes are created by several different mechanisms. 相似文献
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Although used as a therapeutic for 50 years, it is only recently that the application of molecular techniques has provided a basis for understanding growth hormone's (GH) clinical actions. This article reviews progress in our current knowledge of the molecular mechanism of growth hormone (GH) receptor activation based on a number of physicochemical techniques, and documents insights gained into the means used by the activated GH receptor to control the expression of genes regulating growth and metabolism. These findings are related to disorders of short stature, and the therapeutic consequences are summarized. 相似文献
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Soil organic matter and structural stability: mechanisms and implications for management 总被引:61,自引:5,他引:61
J. M. Oades 《Plant and Soil》1984,76(1-3):319-337
Summary The stability of pores and particles is essential for optimum growth of plants. Two categories of aggregates macro- (> 250 m) and micro- (<250 m) depend on organic matter for stability against disruptive forces caused by rapid wetting. Dispersion of clay particles from microaggregates is promoted by adsorption of complexing organic acids which increase the negative charge on clays. The acids are produced by plants, bacteria and fungi. However, the dispersibility of clay in microaggregates is offset by the binding action of polysaccharides, mainly mucilages produced by bacteria, but also by plant roots and fungal hyphae. The stability of microaggregates is also enhanced by multivalent cations which act as bridges between organic colloids and clays. Macroaggregates are enmeshed by plant roots, both living and decomposing, and are thus sensitive to management, and increase in number when grasses are grown and the soil is not disturbed. Lack of root growth,i.e. fallow, has the opposite effect. Various implications for management of soil structure are discussed.Introductory lecture 相似文献
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In bivalves, water-pumping potential is determined both by ciliary activity and by the geometry of the system of passageways that acts as a conduit for water flow. Smooth muscles intrinsic to the gills of eulamellibranch bivalves possess the anatomical organization needed to regulate the dimensions of these water passageways. The tone of these muscles can be controlled experimentally using excitatory neurotransmitters to elicit muscle contraction and by removing Ca++ from the Ringer's solution to induce muscular relaxation. These experimental methods were used to investigate the effects of smooth muscle tone on the gill dimensions of two freshwater bivalves, Dreissena polymorpha and Corbicula fluminea, and one marine bivalve, Mercenaria mercenaria. In addition, endoscopic observations were made from the suprabranchial chamber of a freshwater unionid, Lampsilis anodontoides. Contraction of gill muscles led to a significant reduction in interfilament width, internal ostial area, and the cross-sectional area of the water tubes. Endoscopic observation from minimally disturbed L. anodontoides revealed rapid constriction of the water tubes upon contraction of the muscles of the gill and gill axis. Taken together, these data support the idea that alteration of smooth muscle tone in the gill provides a mechanism for controlling water-pumping activities. 相似文献
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Brdicka T Kadlecek TA Roose JP Pastuszak AW Weiss A 《Molecular and cellular biology》2005,25(12):4924-4933
ZAP-70, a Syk family cytoplasmic protein tyrosine kinase (PTK), is required to couple the activated T-cell antigen receptor (TCR) to downstream signaling pathways. It contains two tandem SH2 domains that bind to phosphorylated TCR subunits and a C-terminal catalytic domain. The region connecting the SH2 domains with the kinase domain, termed interdomain B, has previously been shown to have striking regulatory effects on ZAP-70 function, presumed to be due to the recruitment of key substrates. Paradoxically, deletion of interdomain B preserves ZAP-70 function. Recent structural studies of several receptor tyrosine kinases (RTKs) revealed that their juxtamembrane regions negatively regulate their catalytic activities. In EphB2 and several other RTKs, this autoinhibition depends upon interaction between the kinase domain and tyrosine residues within the juxtamembrane region. Autoinhibition is released when these tyrosines become phosphorylated following receptor stimulation. Sequence homology suggested analogous regulation for ZAP-70. Based on mutagenesis analysis of ZAP-70 interdomain B, we find that this region downregulates ZAP-70 catalytic activity in a similar manner as the juxtamembrane region of EphB2. Similar regulation was also noted for the related Syk kinase. These findings suggest that a general autoinhibitory mechanism employed by RTKs is also used by some cytoplasmic tyrosine kinases. 相似文献
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Delta(9)-Tetrahydrocannabinol (delta(9)-THC), the primary psychoactive constituent of marijuana (Cannabis sativa), is known to bind to two cannabinoid receptors: CB(1) receptors, located primarily in the brain, and CB(2) receptors, located primarily in the periphery. Recent research has suggested that other cannabinoids, including anandamide and WIN 55212-2, may also act at novel non-CB(1), non-CB(2) cannabinoid receptor(s). Anandamide produces a number of in vivo pharmacological effects in CB(1) knockout mice that are not produced by delta(9)-THC and cannot be explained by anandamide's rapid metabolism. In addition, in vitro anandamide and WIN 55212-2 stimulate [35S]GTPgammaS binding in both CB(1) knockout and wildtype mice while delta(9)-THC stimulates this binding only in wildtype mice. Although anandamide and vanilloid agonists share pharmacological effects, anandamide's actions in CB(1) knockout mice do not appear to be mediated by vanilloid VR(1) receptors. While not yet conclusive, these results suggest the possibility of additional cannabinoid receptors in the brain and periphery. 相似文献
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Calcium ions regulate many cellular processes and have important structural roles in living organisms. Despite the great variety of calcium-binding proteins (CaBPs), many of them contain the same Ca(2+)-binding helix-loop-helix structure, referred to as the EF-hand. In the canonical EF-hand, the loop contains three calcium-binding aspartic acid residues, which form the DxDxDG sequence motif, and is flanked by two alpha-helices. Recently, other CaBPs containing the same motif, but lacking one or both helices, have been described. Here, structural motif searches were used to analyse the full diversity of structural context in the known set of DxDxDG-containing CaBPs, including those where the structural resemblance of a given DxDxDG motif to that of EF-hands had not been noted. The results obtained indicate that the EF-hand represents but one, among many, structural context for the DxDxDG-like Ca(2+)-binding loops. While the structural similarity of the binuclear calcium-binding sites in anthrax protective antigen and human thrombospondin suggests that they are homologous, evolutionary relationships for mononuclear sites are harder to discern. The possible scenarios for the evolution of DxDxDG motif-containing calcium-binding loops in a variety of non-homologous proteins suggested loop transplant as a mechanism perhaps responsible for much of the diversity in structural contexts of present day DxDxDG-type CaBPs. Additionally, while it can be shown that existence of a DxDxDG sequence is not enough to confer a conformation suitable for calcium binding, local convergent evolution may still have a role. The analysis presented here has consequences for the prediction of calcium binding from sequence alone. 相似文献
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J Murray-Rust A N McLeod T L Blundell S P Wood 《BioEssays : news and reviews in molecular, cellular and developmental biology》1992,14(5):325-331
Insulin is a member of a family of hormones, growth factors and neuropeptides which are found in both vertebrates and invertebrates. A common 'insulin fold' is probably adopted by all family members. Although the specificities of receptor binding are different, there is a possibility of co-evolution of polypeptides and their receptors. 相似文献
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Hyperpolarizing receptor potentials in lobster olfactory receptor cells: implications for transduction and mixture suppression 总被引:2,自引:1,他引:1
Physiological studies of olfactory receptor cells have focusedon excitatory responses, in part because the evidence for inhibitoryresponses from extracellular recordings, although long-standing,has been equivocal. Intracellular recording from the olfactorycells of two species of lobsters revealed that small but concentrationdependentand repeatable hyperpolarizing receptor potentials could beevoked by a mixture of L-arginine, L-cysteine and L-proline,as well as by histamine. Large, depolarizing receptor potentialswere evoked in the same cells by a complex odor mixture. Simultaneousapplication of depolarizing and hyperpolarizing stimuli reducedthe magnitude of the evoked depolarization. These results implythat multiple, opposing transduction mechanisms are presentin single lobster olfactory receptor cells and reveal a noncompetitivemechanism for peripheral mixture suppression. 相似文献