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81.
A database comprising all ligand-binding sites of known structure aligned with all related protein sequences and structures is described. Currently, the database contains approximately 50000 ligand-binding sites for small molecules found in the Protein Data Bank (PDB). The structure-structure alignments are obtained by the Combinatorial Extension (CE) program (Shindyalov and Bourne, Protein Eng., 11, 739-747, 1998) and sequence-structure alignments are extracted from the ModBase database of comparative protein structure models for all known protein sequences (Sanchez et al., Nucleic Acids Res., 28, 250-253, 2000). It is possible to search for binding sites in LigBase by a variety of criteria. LigBase reports summarize ligand data including relevant structural information from the PDB file, such as ligand type and size, and contain links to all related protein sequences in the TrEMBL database. Residues in the binding sites are graphically depicted for comparison with other structurally defined family members. LigBase provides a resource for the analysis of families of related binding sites. 相似文献
82.
Extrinsic control of developmental diapause in nymphs of prostriate ticks of the subgenus Ixodes sensu stricto (Ixodes ricinus and Ixodes persulcatus from Eurasia and Ixodes scapularis from North America) appears to be based on a complex two-step photoperiodic reaction of a short-day/long-day type. Diapause
control in the subgenus Afrixodes (the South African tick Ixodes rubicundus) appears to be based on a simple long-day reaction. The option between non-diapause development and diapausing arrest in
engorged nymphs is determined by both pre- and post-feeding photoperiodic regimes. Consequently diapausing arrest in engorged
nymphs of Ixodes sensu stricto can be induced either by a short-day (after their engorgement) or by a long-day regime (in unfed nymphs), while active, non-diapause
development is possible only when the short-day pre-feeding regime is followed by a long-day post-feeding regime. The photoperiodic
response in I. (Afrixodes) rubicundus nymphs seems to be of the long-day type both before and after feeding. Consequently this non-diapause development is enabled
by a long-day regime, while diapause is induced by a short-day regime of exposure. Nevertheless, there are some indications
that the control of nymphal diapause in the latter species is also of a complex nature.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
83.
Dragoi V 《Biological cybernetics》2002,86(6):419-426
Simple exposure to repeatitive stimulation is known to induce short-term learning effects across a wide range of species.
These effects can be both suppressive and facilitatory depending on stimulus conditions: repeatitive presentation of a weak
stimulus decreases the strength of the response (habituation), whereas presentation of a tonic stimulus following a series
of weak stimuli transiently increases the response strength (dishabituation). Although these phenomena have been comprehensively
characterized at both behavioral and cellular levels, most existing models of nonassociative learning focus exclusively on
the suppressive or facilitatory changes in response, and do not attempt to relate cellular events to behavior. I propose here
a feedforward model of habituation effects that explains both suppressive and facilitatory changes in response relying on
the interaction between excitatory and inhibitory processes that develop in parallel on two different timescales. The model's
properties are used to explain the rate sensitivity property of habituation and recovery and stimulus dishabituation.
Received: 1 June 2001 / Accepted in revised form: 4 December 2001 相似文献
84.
The conformationally restricted phenylalanine analogue 2-aminoindan-2-phosphonic acid (AIP) inhibits phenylalanine ammonia-lyase (PAL) competitively in a time-dependent manner. This phenomenon was investigated in more detail with the heterologously expressed, highly purified homotetrameric PAL-1 isozyme from parsley. The kinetic analysis revealed that the enzyme-inhibitor complex is formed in a single "slow" step with an association rate of k(2)=2.6+/-0.04 10(4) M(-1) s(-1). The inhibition is reversible with a dissociation rate of k(-2)=1.8+/-0.04 10(-4) s(-1) and an equilibrium constant of K(i)=7+/-2 nM. The previously described PAL inhibitor (S)-2-aminooxy-3-phenylpropanoic acid [(S)-AOPP] was also found to be a slow-binding inhibitor of PAL-1. The carboxyl analogue of AIP, 2-aminoindan-2-carboxylic acid, served as a substrate of PAL-1 and was converted to indene-2-carboxylic acid. 相似文献
85.
The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation 总被引:18,自引:0,他引:18
Pavlov VA Wang H Czura CJ Friedman SG Tracey KJ 《Molecular medicine (Cambridge, Mass.)》2003,9(5-8):125-134
This review outlines the mechanisms underlying the interaction between the nervous and immune systems of the host in response to an immune challenge. The main focus is the cholinergic anti-inflammatory pathway, which we recently described as a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral a7 subunit-containing nicotinic acetylcholine receptors expressed on macrophages. We describe the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system. The clinical implications of this novel mechanism also are discussed. 相似文献
86.
Li Y Johnson G Romine JL Meanwell NA Martin SW Dworetzky SI Boissard CG Gribkoff VK Starrett JE 《Bioorganic & medicinal chemistry letters》2003,13(8):1437-1439
Electrophysiological evaluation of symmetrical analogues of the known maxi-K opener NS-004 (1) led to the discovery of bisphenols 2a, 3a and 4a as openers of cloned maxi-K channels expressed in oocytes. 相似文献
87.
Rodrigues MF Valentin HE Berger PA Tran M Asrar J Gruys KJ Steinbüchel A 《Applied microbiology and biotechnology》2000,53(4):453-460
Burkholderia sp. accumulates polyhydroxyalkanoates (PHAs) containing 3-hydroxybutyrate and 3-hydroxy-4-pentenoic acid when grown on mineral
media under limited phosphate or nitrogen, and using sucrose or gluconate as a carbon and energy source. Solvent fractionation
and NMR spectroscopic characterization of these polyesters revealed the simultaneous accumulation of two homopolyesters rather
than a co-polyester with random sequence distribution of the monomers [Valentin HE, Berger PA, Gruys KJ, Rodrigues MFA, Steinbüchel
A, Tran M, Asrar J (1999) Macromolecules 32: 7389–7395]. To understand the genetic requirements for such unusual polyester
accumulation, we probed total genomic DNA from Burkholderia sp. by Southern hybridization experiments using phaC-specific probes. These experiments indicated the presence of more than one PHA synthase gene within the genome of Burkholderia sp. However, when total genomic DNA from Burkholderia sp. was used to complement a PHA-negative mutant of Ralstonia eutropha for PHA accumulation, only one PHA synthase gene was obtained resembling the R. eutropha type of PHA synthases, based on amino acid sequence similarity. In addition to the PHA synthase gene, based on high sequence
homology, genes encoding a β-ketothiolase and acetoacetyl-CoA reductase were identified in a gene cluster with the PHA synthase
gene. The arrangement of the three genes is quite similar to the R. eutropha poly-β-hydroxybutyrate biosynthesis operon.
Received: 3 September 1999 / Received revision: 29 October 1999 / Accepted: 5 November 1999 相似文献
88.
Inhibition of soluble guanylate cyclase by ODQ 总被引:6,自引:0,他引:6
Zhao Y Brandish PE Di Valentin M DiValentin M Schelvis JP Babcock GT Marletta MA 《Biochemistry》2000,39(35):10848-10854
The heme in soluble guanylate cyclases (sGC) as isolated is ferrous, high-spin, and 5-coordinate. [1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one] (ODQ) has been used extensively as a specific inhibitor for sGC and as a diagnostic tool for identifying a role for sGC in signal transduction events. Addition of ODQ to ferrous sGC leads to a Soret shift from 431 to 392 nm and a decrease in nitric oxide (NO)-stimulated sGC activity. This Soret shift is consistent with oxidation of the ferrous heme to ferric heme. The results reported here further define the molecular mechanism of inhibition of sGC by ODQ. Addition of ODQ to the isolated sGC heme domain [beta1(1-385)] gave the same spectral changes as when sGC was treated with ODQ. EPR and resonance Raman spectroscopy was used to show that the heme in ODQ-treated beta1(1-385) is indeed ferric. Inhibition of the NO-stimulated sGC activity by ODQ is due to oxidation of the sGC heme and not to perturbation of the catalytic site, since the ODQ-treated sGC has the same basal activity as untreated sGC (68 +/- 12 nmol min(-)(1) mg(-)(1)). In addition, ODQ-oxidized sGC can be re-reduced by dithionite, and this re-reduced sGC has identical NO-stimulated activity as the original ferrous sGC. Oxidation of the sGC heme by ODQ is fast with a second-order rate constant of 8.5 x 10(3) M(-)(1) s(-)(1). ODQ can also oxidize hemoglobin, indicating that the reaction is not specific for the heme in sGC versus that in other hemoproteins. 相似文献
89.
Enomoto A Murakami M Valentin E Lambeau G Gelb MH Kudo I 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(7):4007-4014
We herein demonstrate that mast cells express all known members of the group II subfamily of secretory phospholipase A2 (sPLA2) isozymes, and those having heparin affinity markedly enhance the exocytotic response. Rat mastocytoma RBL-2H3 cells transfected with heparin-binding (sPLA2-IIA, -V, and -IID), but not heparin-nonbinding (sPLA2-IIC), enzymes released more granule-associated markers (beta-hexosaminidase and histamine) than mock- or cytosolic PLA2alpha (cPLA2alpha)-transfected cells after stimulation with IgE and Ag. Site-directed mutagenesis of sPLA2-IIA and -V revealed that both the catalytic and heparin-binding domains are essential for this function. Confocal laser and electron microscopic analyses revealed that sPLA2-IIA, which was stored in secretory granules in unstimulated cells, accumulated on the membranous sites where fusion between the plasma membrane and granule membranes occurred in activated cells. These results suggest that the heparin-binding sPLA2s bind to the perigranular membranes through their heparin-binding domain, and lysophospholipids produced in situ by their enzymatic action may facilitate the ongoing membrane fusion. In contrast to the redundant role of sPLA2-IIA, -IID, and -V in the regulation of degranulation, only sPLA2-V had the ability to markedly augment IgE/Ag-stimulated immediate PGD2 production, which reached a level comparable to that elicited by cPLA2alpha. The latter observation reveals an unexplored functional segregation among the three related isozymes expressed in the same cell population. 相似文献
90.
What can venom phospholipases A(2) tell us about the functional diversity of mammalian secreted phospholipases A(2)? 总被引:3,自引:0,他引:3
Most venomous animals including snakes, bees and scorpions contain a variety of venom phospholipases A(2) (vPLA(2)s) which participate in both digestion of prey and venom toxicity. So far, more than 150 vPLA(2)s have been characterized. They all have a conserved fold with several disulfide bridges, can be catalytically active or not, and several of them can display a tremendous array of toxic effects including neurotoxicity and myotoxicity. Furthermore, the molecular diversity of vPLA(2)s found within a single snake venom can result from positive Darwinian selection. Over the last decade, receptors and binding proteins for vPLA(2)s have been identified in mammals, suggesting that vPLA(2)s can exert their toxicities through specific protein-protein interactions, besides their catalytic activity. The brain N-type receptors are involved in the neurotoxicity of vPLA(2)s, but are not yet cloned. The M-type receptor has been cloned from skeletal muscle, belongs to the superfamily of C-type lectins, and interestingly, has homology with vPLA(2) inhibitors purified from snake blood. The molecular diversity of vPLA(2)s and the presence of receptors for vPLA(2)s in mammals raises the possibility that there is also a diversity of mammalian secreted PLA(2)s (msPLA(2)s) which are the normal endogenous ligands of the vPLA(2) receptors. This view led us to clone five novel msPLA(2)s (IID, IIE, IIF, III, and X msPLA(2)s), which together with the previously cloned msPLA(2)s (IB, IIA, IIC, and V), indicate that mammals also express a large diversity of sPLA(2)s. M-type receptors can have IB and IIA msPLA(2)s as natural endogenous ligands, suggesting that msPLA(2)s, like vPLA(2)s, can function as both enzymes and ligands. msPLA(2)s were first implicated in lipid digestion, and more recently in host defense mechanisms including inflammation and antibacterial defense. The growing molecular diversity of msPLA(2)s, which all have a specific tissue distribution, and the presence of receptors suggest that msPLA(2)s, like vPLA(2)s, are endowed with a wide array of biological effects which remain to be discovered. 相似文献