共查询到20条相似文献，搜索用时 31 毫秒
1.
Jaakola VP Griffith MT Hanson MA Cherezov V Chien EY Lane JR Ijzerman AP Stevens RC 《Science (New York, N.Y.)》2008,322(5905):1211-1217
The adenosine class of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) mediates the important role of extracellular adenosine in many physiological processes and is antagonized by caffeine. We have determined the crystal structure of the human A2A adenosine receptor, in complex with a high-affinity subtype-selective antagonist, ZM241385, to 2.6 angstrom resolution. Four disulfide bridges in the extracellular domain, combined with a subtle repacking of the transmembrane helices relative to the adrenergic and rhodopsin receptor structures, define a pocket distinct from that of other structurally determined GPCRs. The arrangement allows for the binding of the antagonist in an extended conformation, perpendicular to the membrane plane. The binding site highlights an integral role for the extracellular loops, together with the helical core, in ligand recognition by this class of GPCRs and suggests a role for ZM241385 in restricting the movement of a tryptophan residue important in the activation mechanism of the class A receptors. 相似文献
2.
Shen WL Kwon Y Adegbola AA Luo J Chess A Montell C 《Science (New York, N.Y.)》2011,331(6022):1333-1336
Many animals, including the fruit fly, are sensitive to small differences in ambient temperature. The ability of Drosophila larvae to choose their ideal temperature (18°C) over other comfortable temperatures (19° to 24°C) depends on a thermosensory signaling pathway that includes a heterotrimeric guanine nucleotide-binding protein (G protein), a phospholipase C, and the transient receptor potential TRPA1 channel. We report that mutation of the gene (ninaE) encoding a classical G protein-coupled receptor (GPCR), Drosophila rhodopsin, eliminates thermotactic discrimination in the comfortable temperature range. This role for rhodopsin in thermotaxis toward 18°C was light-independent. Introduction of mouse melanopsin restored normal thermotactic behavior in ninaE mutant larvae. We propose that rhodopsins represent a class of evolutionarily conserved GPCRs that are required for initiating thermosensory signaling cascades. 相似文献
3.
G-protein coupled receptors（GPCRs） have a relatively conservative seven transmembrane helix（7tm） regions, and their N and C termini are various. In order to strengthen the features of GPCR families, N and C termini were removed in this study, then frequency features in the form of single amino acid and dipeptide compositions for recognition of human GPCRs were analyzed and extracted based on the compressed amino acid alphabets. Based on these features, classifiers were developed using support vector machine（SVM）. The ability of different compressed methods was investigated. The testing results demonstrated that the suitable choice of compressed method combined with amino acid composition information could get good performance for the recognition of human GPCRs. 相似文献
4.
G protein-coupled receptors in Anopheles gambiae 总被引：3，自引：0，他引：3
Hill CA Fox AN Pitts RJ Kent LB Tan PL Chrystal MA Cravchik A Collins FH Robertson HM Zwiebel LJ 《Science (New York, N.Y.)》2002,298(5591):176-178
We used bioinformatic approaches to identify a total of 276 G protein-coupled receptors (GPCRs) from the Anopheles gambiae genome. These include GPCRs that are likely to play roles in pathways affecting almost every aspect of the mosquito's life cycle. Seventy-nine candidate odorant receptors were characterized for tissue expression and, along with 76 putative gustatory receptors, for their molecular evolution relative to Drosophila melanogaster. Examples of lineage-specific gene expansions were observed as well as a single instance of unusually high sequence conservation. 相似文献
5.
Wang Q Zhao J Brady AE Feng J Allen PB Lefkowitz RJ Greengard P Limbird LE 《Science (New York, N.Y.)》2004,304(5679):1940-1944
Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) association with receptor-Gbetagamma complexes, spinophilin reduces arrestin-stabilized receptor phosphorylation, receptor endocytosis, and the acceleration of mitogen-activated protein kinase (MAPK) activity following endocytosis. Spinophilin knockout mice were more sensitive than wild-type mice to sedation elicited by stimulation of alpha2 adrenergic receptors, whereas arrestin 3 knockout mice were more resistant, indicating that the signal-promoting, rather than the signal-terminating, roles of arrestin are more important for certain response pathways. The reciprocal interactions of GPCRs with spinophilin and arrestin represent a regulatory mechanism for fine-tuning complex receptor-orchestrated cell signaling and responses. 相似文献
6.
W Liu E Chun AA Thompson P Chubukov F Xu V Katritch GW Han CB Roth LH Heitman AP IJzerman V Cherezov RC Stevens 《Science (New York, N.Y.)》2012,337(6091):232-236
Pharmacological responses of G protein-coupled receptors (GPCRs) can be fine-tuned by allosteric modulators. Structural studies of such effects have been limited due to the medium resolution of GPCR structures. We reengineered the human A(2A) adenosine receptor by replacing its third intracellular loop with apocytochrome b(562)RIL and solved the structure at 1.8 angstrom resolution. The high-resolution structure allowed us to identify 57 ordered water molecules inside the receptor comprising three major clusters. The central cluster harbors a putative sodium ion bound to the highly conserved aspartate residue Asp(2.50). Additionally, two cholesterols stabilize the conformation of helix VI, and one of 23 ordered lipids intercalates inside the ligand-binding pocket. These high-resolution details shed light on the potential role of structured water molecules, sodium ions, and lipids/cholesterol in GPCR stabilization and function. 相似文献
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8.
Rosenbaum DM Cherezov V Hanson MA Rasmussen SG Thian FS Kobilka TS Choi HJ Yao XJ Weis WI Stevens RC Kobilka BK 《Science (New York, N.Y.)》2007,318(5854):1266-1273
The beta2-adrenergic receptor (beta2AR) is a well-studied prototype for heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) that respond to diffusible hormones and neurotransmitters. To overcome the structural flexibility of the beta2AR and to facilitate its crystallization, we engineered a beta2AR fusion protein in which T4 lysozyme (T4L) replaces most of the third intracellular loop of the GPCR ("beta2AR-T4L") and showed that this protein retains near-native pharmacologic properties. Analysis of adrenergic receptor ligand-binding mutants within the context of the reported high-resolution structure of beta2AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Amino acids known to regulate receptor function are linked through packing interactions and a network of hydrogen bonds, suggesting a conformational pathway from the ligand-binding pocket to regions that interact with G proteins. 相似文献
9.
Extracellular ligand binding to G protein-coupled receptors (GPCRs) modulates G protein and β-arrestin signaling by changing the conformational states of the cytoplasmic region of the receptor. Using site-specific (19)F-NMR (fluorine-19 nuclear magnetic resonance) labels in the β(2)-adrenergic receptor (β(2)AR) in complexes with various ligands, we observed that the cytoplasmic ends of helices VI and VII adopt two major conformational states. Changes in the NMR signals reveal that agonist binding primarily shifts the equilibrium toward the G protein-specific active state of helix VI. In contrast, β-arrestin-biased ligands predominantly impact the conformational states of helix VII. The selective effects of different ligands on the conformational equilibria involving helices VI and VII provide insights into the long-range structural plasticity of β(2)AR in partial and biased agonist signaling. 相似文献
10.
The process of polar auxin transport, central to a plant's auxin relations, can be inhibited by a group of synthetic compounds that apparently act by binding to a plasma membrane protein known as the naphthylphthalamic acid (NPA) receptor. No endogenous ligand to the NPA receptor, capable of affecting polar auxin transport in plants, has yet been found. It is now shown that a group of flavonoids-including quercetin, apigenin, and kaempferol-can specifically compete with [(3)H]NPA for binding to its receptor and can perturb auxin transport in a variety of plant tissues and transport systems in a manner closely paralleling the action of synthetic transport inhibitors. Because the active flavonoids are widely distributed in the plant kingdom and exert their effects at micromolar concentrations approximating likely endogenous levels, they may act as natural auxin transport regulators in plants. 相似文献
11.
Styer KL Singh V Macosko E Steele SE Bargmann CI Aballay A 《Science (New York, N.Y.)》2008,322(5900):460-464
A large body of evidence indicates that metazoan innate immunity is regulated by the nervous system, but the mechanisms involved in the process and the biological importance of such control remain unclear. We show that a neural circuit involving npr-1, which encodes a G protein-coupled receptor (GPCR) related to mammalian neuropeptide Y receptors, functions to suppress innate immune responses. The immune inhibitory function requires a guanosine 3',5'-monophosphate-gated ion channel encoded by tax-2 and tax-4 as well as the soluble guanylate cyclase GCY-35. Furthermore, we show that npr-1- and gcy-35-expressing sensory neurons actively suppress immune responses of nonneuronal tissues. A full-genome microarray analysis on animals with altered neural function due to mutation in npr-1 shows an enrichment in genes that are markers of innate immune responses, including those regulated by a conserved PMK-1/p38 mitogen-activated protein kinase signaling pathway. These results present evidence that neurons directly control innate immunity in C. elegans, suggesting that GPCRs may participate in neural circuits that receive inputs from either pathogens or infected sites and integrate them to coordinate appropriate immune responses. 相似文献
12.
CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, is expressed on antigen-presenting cells (APCs) and is essential for immune activation. Although agonistic CD40 antibodies have been developed for immunotherapy, their clinical efficacy has been limited. We have found that coengagement of the Fc domain of agonistic CD40 monoclonal antibodies (mAbs) with the inhibitory Fcγ receptor FcγRIIB is required for immune activation. Direct comparison of mAbs to CD40 enhanced for activating FcγR binding, hence capable of cytotoxicity, or for inhibitory FcγRIIB binding, revealed that enhancing FcγRIIB binding conferred immunostimulatory activity and considerably greater anti-tumor responses. This unexpected requirement for FcγRIIB in enhancing CD40-mediated immune activation has direct implications for the design of agonistic antibodies to TNFR as therapeutics. 相似文献
13.
Crystal structure of rhodopsin: A G protein-coupled receptor 总被引：2，自引：0，他引：2
Palczewski K Kumasaka T Hori T Behnke CA Motoshima H Fox BA Le Trong I Teller DC Okada T Stenkamp RE Yamamoto M Miyano M 《Science (New York, N.Y.)》2000,289(5480):739-745
Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) respond to a variety of different external stimuli and activate G proteins. GPCRs share many structural features, including a bundle of seven transmembrane alpha helices connected by six loops of varying lengths. We determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution. The highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the seven-helix transmembrane motif. The ground-state chromophore, 11-cis-retinal, holds the transmembrane region of the protein in the inactive conformation. Interactions of the chromophore with a cluster of key residues determine the wavelength of the maximum absorption. Changes in these interactions among rhodopsins facilitate color discrimination. Identification of a set of residues that mediate interactions between the transmembrane helices and the cytoplasmic surface, where G-protein activation occurs, also suggests a possible structural change upon photoactivation. 相似文献
14.
Molecular biology of synaptic receptors 总被引：18，自引：0，他引：18
E De Robertis 《Science (New York, N.Y.)》1971,171(975):963-971
A special proteolipid (a hydrophobic protein) has been extracted and purified from nerve-ending membranes and total particulate matter of gray areas of the central nervous system. Such a proteolipid shows a high affinity for binding d-tubocurarine, serotonin, and atropine and has been called receptor proteolipid. The interaction of this proteolipid with atropine sulfate was studied with light scattering and polarization of fluorescence. The changes observed, which follow a cooperative type of curve, were attributed to the aggregation of the proteolipid macromolecules. Such a phenomenon was then observed under the electron microscope. A receptor proteolipid having a high affinity for binding acetylcholine, hexamethonium, and other cholinergic drugs was isolated and purified from electric tissue of fishes and from electroplax membranes. Such a proteolipid was also extracted from membranes from which acetylcholinesterase had been removed, and it was concluded that this enzyme and the receptor proteolipid are two different macromolecules. A high affinity binding site with a dissociation constant of K1 equal to 10(-7) and about ten sites with K2 equal to 10(-5) were recognized in the receptor proteolipid. Under the electron microscope the receptor proteolipid of brain appears as a rod-shaped macromolecule which may assume paracrystalline arrays with 10(-8) molar atropine sulfate. Similarly the receptor proteolipid from electric tissue and from skeletal muscle may form paracrystalline arrays under the action of acetylcholine and hexamethonium. A model of the cholinergic receptor based on the properties of the proteolipid is presented. Preliminary work indicates the possibility of obtaining a biophysical response to acetylcholine when the receptor proteolipid is embedded in artificial bilayered lipid membrance. 相似文献
15.
Lalani AS Masters J Zeng W Barrett J Pannu R Everett H Arendt CW McFadden G 《Science (New York, N.Y.)》1999,286(5446):1968-1971
Chemokine receptors serve as portals of entry for certain intracellular pathogens, most notably human immunodeficiency virus (HIV). Myxoma virus is a member of the poxvirus family that induces a lethal systemic disease in rabbits, but no poxvirus receptor has ever been defined. Rodent fibroblasts (3T3) that cannot be infected with myxoma virus could be made fully permissive for myxoma virus infection by expression of any one of several human chemokine receptors, including CCR1, CCR5, and CXCR4. Conversely, infection of 3T3-CCR5 cells can be inhibited by RANTES, anti-CCR5 polyclonal antibody, or herbimycin A but not by monoclonal antibodies that block HIV-1 infection or by pertussis toxin. These findings suggest that poxviruses, like HIV, are able to use chemokine receptors to infect specific cell subtypes, notably migratory leukocytes, but that their mechanisms of receptor interactions are distinct. 相似文献
16.
Caloric restriction has been shown to increase longevity in organisms ranging from yeast to mammals. In some organisms, this has been associated with a decreased fat mass and alterations in insulin/insulin-like growth factor 1 (IGF-1) pathways. To further explore these associations with enhanced longevity, we studied mice with a fat-specific insulin receptor knockout (FIRKO). These animals have reduced fat mass and are protected against age-related obesity and its subsequent metabolic abnormalities, although their food intake is normal. Both male and female FIRKO mice were found to have an increase in mean life-span of approximately 134 days (18%), with parallel increases in median and maximum life-spans. Thus, a reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling. 相似文献
17.
Receptors for the age of anxiety: pharmacology of the benzodiazepines 总被引：40，自引：0，他引：40
Investigation of the actions of the benzodiazepines has provided insights into the neurochemical mechanisms underlying anxiety, seizures, muscle relaxation, and sedation. Behavioral, electrophysical, pharmacological, and biochemical evidence indicates that the benzodiazepines exert their therapeutic effects by interacting with a high-affinity binding site (receptor) in the brain. The benzodiazepine receptor interacts with a receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter, and enhances its inhibitory effects. The benzodiazepine receptor may also interact with endogenous substances and several naturally occurring compounds, including the purines and nicotinamide, are candidates for this role. Both the purines and nicotinamide possess some benzodiazepine-like properties in vivo, although further work will be required to confirm their possible roles as endogenous benzodiazepines. 相似文献
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It has been proposed that dithiol-disulfide interchange and oxidation-reduction reactions may play a role in hormone-induced receptor activation. Inspection of the sequences of the gonadotropic hormones revealed a homologous tetrapeptide (Cys-Gly-Pro-Cys) between the beta subunit of lutropin (LH) and the active site of thioredoxin (TD). The beta subunit of follitropin (FSH) has a similar sequence (Cys-Gly-Lys-Cys). Thioredoxin is a ubiquitous protein serving as an electron donor for ribonucleotide reductase, but it also exhibits disulfide isomerase activity. The catalytic activity of TD was assayed by its ability to reactivate reduced and denatured ribonuclease. In this assay, the purified ovine FSH and bovine LH preparations tested were approximately 60 and approximately 300 times, respectively, as active as TD on a molar basis. This heretofore unsuspected catalytic property of FSH and LH may be important in understanding their mechanism of receptor activation and signal transduction. 相似文献
20.
Gong R Ding C Hu J Lu Y Liu F Mann E Xu F Cohen MB Luo M 《Science (New York, N.Y.)》2011,333(6049):1642-1646
Midbrain dopamine neurons regulate many important behavioral processes, and their dysfunctions are associated with several human neuropsychiatric disorders such as attention deficit hyperactivity disorder (ADHD) and schizophrenia. Here, we report that these neurons in mice selectively express guanylyl cyclase-C (GC-C), a membrane receptor previously thought to be expressed mainly in the intestine. GC-C activation potentiates the excitatory responses mediated by glutamate and acetylcholine receptors via the activity of guanosine 3',5'-monophosphate-dependent protein kinase (PKG). Mice in which GC-C has been knocked out exhibit hyperactivity and attention deficits. Moreover, their behavioral phenotypes are reversed by ADHD therapeutics and a PKG activator. These results indicate important behavioral and physiological functions for the GC-C/PKG signaling pathway within the brain and suggest new therapeutic targets for neuropsychiatric disorders related to the malfunctions of midbrain dopamine neurons. 相似文献