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排序方式: 共有142条查询结果,搜索用时 15 毫秒
1.
2.
Jean Quancard Philippe Karoyan Sandrine Sagan Odile Convert Solange Lavielle Gérard Chassaing Olivier Lequin 《European journal of biochemistry》2003,270(13):2869-2878
Residue Leu10 of substance P (SP) is critical for NK-1 receptor recognition and agonist activity. In order to probe the bioactive conformation of this residue, cis- and trans-3-substituted prolinoleucines were introduced in position 10 of SP. The substituted SP analogues were tested for their affinity to human NK-1 receptor specific binding sites (NK-1M and NK-1m) and their potency to stimulate adenylate cyclase and phospholipase C in CHO cells transfected with the human NK-1 receptor. [trans-3-prolinoleucine10]SP retained affinity and potency similar to SP whereas [cis-3-prolinoleucine10]SP shows dramatic loss of affinity and potency. To analyze the structural implications of these biological results, the conformational preferences of the SP analogues were analyzed by NMR spectroscopy and minimum-energy conformers of Ac-cis-3-prolinoleucine-NHMe, Ac-trans-3-prolinoleucine-NHMe and model dipeptides were generated by molecular mechanics calculations. From NMR and modeling studies it can be proposed that residue Leu10 of SP adopts a gauche(+) conformation around the chi1 angle and a trans conformation around the chi2 angle in the bioactive conformation. Together with previously published results, our data indicate that the C-terminal SP tripeptide should preferentially adopt an extended conformation or a PPII helical structure when bound to the receptor. 相似文献
3.
Sandrine Sagan Hubert Josien Philippe Karoyan Alié Brunissen Gérard Chassaing Solange Lavielle 《Bioorganic & medicinal chemistry》1996,4(12):2167-2178
The action of rotameric probes introduced either in position 7 or 8 in the sequence of substance P (SP) was investigated, i.e.
-tetrahydroisoquinoleic acid (Tic),
-fluorenylglycine (Flg),
-diphenylalanine (Dip), the diastereoisomers of
-1-indanylglycine (Ing) and
-benz[ƒ]indanylglycine (Bfi), the Z- and E-isomers of dehydrophenylalanine and dehydronaphthylalanine (ΔZPhe, ΔEPhe, ΔZNal, ΔENal) and
(Dmp). The aim of this study was the topographical characterization of the binding subsites of human NK-1 receptor expressed in CHO cells, especially the S7 and S8 subsites, corresponding to residues Phe7 and Phe8 of substance P. According to the binding potencies of these substituted-SP analogues, the S7 binding subsite is smaller than the S8 subsite: the S7 subsite accepts only one aromatic nucleus, while the S8 can accommodate three coplanar nuclei altogether. These findings are compatible with the idea that the S8 binding subsite may reside in the extracellular loops of the hNK-1 receptor. NK-1 agonists bind to human NK-1 receptor and activate the production of both inositol phosphates and cyclic AMP. As already quoted for septide, [pGlu6, Pro9]SP(6–11), discrepancies are observed between affinity (Ki) and activity (EC50) values for IPs production. While a weak correlation between Ki and EC50 values for IPs production could be found (r = 0.70), an excellent correlation could be demonstrated between their affinities (Ki) and their potencies (EC50) for cAMP production (r = 0.97). The high potency (EC50) observed for ‘septide-like’ molecules on PI hydrolysis, compared to their affinity is not an artefact related to the high level of NK-1 receptors expressed on CHO cells since a good correlation was found between EC50 values obtained for PI hydrolysis and those measured for spasmogenic activity in guinea pig ileum bioassay (r = 0.94).
According to the binding potencies of constrained analogues of phenylalanine, the S7 binding subsite of human NK-1 receptor is small, whereas the S8, which can accommodate three coplanar nuclei, might probably reside in the extracellular loop. The discrepancies observed between affinity (Ki) and activity (EC50) values for IPs production are not an artefact of CHO cells since a good correlation was found between EC50 for PI hydrolysis and those measured in guinea pig ileum bioassay. 相似文献
4.
S Charpentier S Sagan A Delfour P Nicolas 《Biochemical and biophysical research communications》1991,179(3):1161-1168
Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2), dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2) and deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) are the first naturally occurring peptides highly potent for and almost specific to the mu- and delta-opioid receptors, respectively. The amino-terminal domains Tyr-D-X-Phe (where X is either Ala or Met) of these peptides behave as selective and potent mu-receptor ligands. Routing of Tyr-D-X-Phe to the delta- or the mu- receptor is associated with the presence or the absence at the C-terminus of an additional hydrophobic and negatively charged tetrapeptide by-passing the mu-addressing ability of the amino-terminal moiety. A study of 20 Tyr-D-X-Phe-Y-NH2 analogs with substitution of X and Y by neutral, hydrophobic, aromatic amino acids as well as by charged amino acid residues shows that tetrapeptides maintain high binding affinity and selectivity for the mu-opioid receptor. Although residue in position 4 serves a delta-address function, the tripeptide motif at the C-terminus of dermenkephalin and deltorphin I are critical components for high selectivity at delta-opioid receptor. Results demonstrate that mu- and delta-opioid receptors share topologically equivalent ligand-binding domains, or ligand-binding sequences similarities, that recognized Tyr-D-X-Phe as a consensus message-binding sequence. The delta-receptor additionally contains a unique address subsite at or near the conserved binding domain that accommodates the C-terminal tetrapeptide motif of dermenkephalin and deltorphin I. 相似文献
5.
6.
Two non-stoichiometric binding sites had previously been characterized for the NK-1 receptor using two different types of radiolabelled analogues of substance P. However, the question remained on their eventual conformational interconversion induced or not by the ligand. In this study, kinetic, saturation, and competition studies using [3H]propionyl[Pro(9)]SP demonstrate the existence of two independent binding components in CHO cells transfected with the human NK-1 receptor, with K(d) values of 0.040 nM ( approximately 20% of total sites) and 5.9 nM ( approximately 80% of total sites) that correspond to those of the two previously described binding sites. These two binding sites do not seem to interconvert since the minor one can be selectively extinguished in saturation studies in the presence of a SP analogue specific of this binding site. 相似文献
7.
8.
Sachon E Bolbach G Chassaing G Lavielle S Sagan S 《The Journal of biological chemistry》2002,277(52):50409-50414
Analogs of substance P (H-RPKPQQFFGLM-NH(2)) incorporating a photoreactive para-benzoyl-l-phenylalanine (p-Bzl)Phe at position 4, 5, 6, 9, or 10 of the sequence have been synthesized and pharmacologically characterized previously as full NK-1 receptor agonists. In this study we show that all analogs, [BAPA(0), (p-Bzl)Phe(x), Met(O(2))(11)]SP also display high yields (40-70%) of NK-1 receptor photolabeling. To identify the site of photoinsertion in the receptor, covalent ligand/receptor complexes were digested with enzymes or chemically cleaved with cyanogen bromide and purified with streptavidin-coated magnetic beads before matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry analysis. Only the analog photoreactive at position 5 gave irreversible, reproducible, and unequivocal covalent linkage. Sequential digestions of the covalent complex, substance P analog photoreactive at position 5/NK-1 receptor, with trypsin, endo-GluC and carboxypeptidase Y, led to the identification of the tripeptide (173)TMP(175) in the second extracellular loop of the hNK-1 receptor as the site of photoinsertion. Reaction of cyanogen bromide on the pentapeptide TMPSR did not yield the expected cleavage on the carboxylic side of methionine. The high precision of mass spectrometry analysis on the mass measured led us to determine that C(gamma)H(2) of Met(174) was the site of covalent linkage of the photoreactive substance P analog. Such an insertion (photolinked ligand) on its C(gamma)H(2) renders methionine refractory to CNBr cleavage. 相似文献
9.
Sphingoid base synthesis requirement for endocytosis in Saccharomyces cerevisiae 总被引:4,自引:0,他引:4
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Zanolari B Friant S Funato K Sütterlin C Stevenson BJ Riezman H 《The EMBO journal》2000,19(12):2824-2833
The internalization step of endocytosis in yeast requires actin and sterols for maximum efficiency. In addition, many receptors and plasma membrane proteins must be phosphorylated and ubiquitylated prior to internalization. The Saccharomyces cerevisiae end8-1 mutant is allelic to lcb1, a mutant defective in the first step of sphingoid base synthesis. Upon arrest of sphingoid base synthesis a rapid block in endocytosis is seen. This block can be overcome by exogenous sphingoid base. Under conditions where endogenous sphingosine base synthesis was blocked and exogenous sphingoid bases could not be converted to phosphorylated sphingoid bases or to ceramide, sphingoid bases could still suppress the endocytic defect. Therefore, the required lipid is most likely a sphingoid base. Interestingly, sphingoid base synthesis is required for proper actin organization, but is not required for receptor phosphorylation. This is the first case of a physiological role for sphingoid base synthesis, other than as a precursor for ceramide or phosphorylated sphingoid base synthesis. 相似文献
10.
Eichholtz-Wirth H Sagan D 《Apoptosis : an international journal on programmed cell death》2000,5(3):255-263
Fractionated -irradiation (15 × 2 Gy in 3 weeks) induces a cellular resistance in HeLa cells against cisplatin exposure but not against irradiation. The mechanisms underlying this cellular resistance are associated with major changes in the TNFR1-dependent transduction pathway. The resistant HeLa/B cells exhibit increased levels of NF-B with temporally independent regulation of the subunits NF-B50 and NF-B65. Blocking IB degradation by the proteasome inhibitor PSI, which abolishes the release of the active NF-B protein, induces cell death much more effectively in the parental than in the resistant HeLa/B cells. The translocation of NF-B does not seem to be affected in a similar manner since masking of the translocation sequence by NF-B SN50 enhances cisplatin toxicity to the same degree in both cell lines and overcomes drug resistance. Changes in upstream signaling are suggested by increased sensitivity of the parental HeLa cells to cisplatin in the presence of neutralizing anti-TNFR1. In HeLa/B cells, reduced expression of the 50 kDa silencer of death domain, SODD, is accompanied by constitutive overexpression of a 40–42 kDa SODD-like protein. A possible involvement of SODD in cisplatin resistance is discussed, which may shift the balance between life and death in the TNF receptor pathway to increased NF-B activation. 相似文献