Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The conformational properties of some somatostatin fragments have been studied using high resolution NMR and semi-empirical calculations. The fragments are Thr10-Phe11, Phe11-Thr12, Thr10-Phe11-Thr12 and Thr10-Phe11-Thr12-Ser13. The results of high resolution 1H and 13C NMR using dimethylsulfoxide and 2H2O as solvents, combined with a new method for determining dihedral angles phi and psi from 13C and 1H spin lattice relaxation times are presented. A marked inequivalence of the two Thr10,12 residues is attributed to a shielding of the the Thr10 side chain by the Phe11 aromatic ring. The calculations show the existence of extended and folded low energy conformations in the tri and tetrapeptide. Only the folded structures give the observed shielding of Thr10. A temperature study of the tri and the tetrapeptide indicates that the folded structures are energetically the most favorable conformations at room temperature in dimethylsulfoxide. Increasing temperature reduces the nonequivalence of the Thr residues towards the differences that are observed in 2H2O. A detailed comparison of 3JalphaNH coupling constants and relaxation time measurements with the calculated conformations gives in general good agreement between both approaches. It is concluded that in these linear peptides, although several quite different low energy conformations exist, some of them are predominant. The continuity of both NMR parameters and calculated low energy conformations, when going from the smaller to the larger peptides, demonstrates the existence of structural properties far from the "random conformation".
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PMID:The conformational properties of some fragments of the peptide hormone somatostatin. 42 18

The results of a conformational study on the C terminal hexapeptide of Somatostatin are presented. Semi-empirical energy calculations and high resolution NMR methods have been used to obtain information on the conformational properties of SRIF9-14 in [2H6]dimethylsulfoxide and 2H2O. It is concluded from the energy calculations that the peptide has an averaged conformation in which semi extended and folded structures are important. Only some of the folded conformations can explain the chemical shift differences between the amino acid residues Thr10 and Thr12 as a ring current shift by the Phe11 aromatic ring on Thr10. The nonequivalence is more pronounced in dimethyl-sulfoxide (0.23--0.15 ppm) where it decreases with increasing temperature towards the temperature independent value in 2H2O (0.03 ppm). This suggests that the folded conformations are somewhat predominant in dimethylsulfoxide solutions. In 2H2O the semi extended and folded structures are statistically equally important and the peptide is more flexible. A comparison with a study on the smaller fragments SRIF10-12 and SRIF10-13 which have similar conformational properties, demonstrates the usefulness of the fragment approach in conformational studies of peptides.
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PMID:Conformational studies on somatostatin. II. The C-terminal hexapeptide fragment. 51 2

Twenty cyclic and linear analogues of somatostatin have been compared with respect to their conformational behavior and biological activity. It appears that all active compounds have in common a well defined, predominant backbone conformation. For linear peptides, this conformation can only be detected at low (-80 degrees C) temperature by NMR measurements. Selectivity is suggested to be determined by the nature and topology of the side chains linked to this common backbone conformation. The side chain conformation is also only accessible for NOE measurements in the low temperature range.
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PMID:Backbone modifications in somatostatin analogues: relation between conformation and activity. 135 71

A modern method is reported for the assignment of absolute configuration for peptidomimetics in bioactive peptides by use of 1H-NMR parameters in solution. Four peptide systems incorporating either retro-inverso modifications or 2-aminocyclopentanecarboxylic acid (2-Ac5c) as a peptidomimetic for proline are discussed. (1) Two 14-membered cyclic dermorphin analogs Tyr-c[D-A2bu-Phe-gPhe-(S and R)-mLeu] with a reverse amide bond between gPhe and mLeu residues where gPhe denotes a gem-diamino analog of Phe and mLeu refers to a malonyl analog of Leu. (2) Two cyclic hexapeptides related to somatostatin, c[gSar6-(S and R)-mPhe7-D-Trp8-Lys9-Thr10-Phe11], with a reverse amide bond between the gSar and mPhe residues where the gSar and mPhe denote the gemdiamino and malonyl analogs of the Sar and Phe residues, respectively. The superscript numbers refer to positions in native somatostatin. (3) Cyclic hexapeptide somatostatin analogs containing 2-Ac5c [trans-(1S,2S)-2-Ac5c, trans-(1R,2R)-2-Ac5c,cis-(1R,2S)-2-Ac5c, and cis-(1S,2R)-2-Ac5c] in place of proline c[(2-Ac5c)6-Phe7-D-Trp8-Lys9-Thr10-Phe11]. (4) Morphiceptin related analogs incorporating a cis-2-Ac5c residue as shown in Tyr-cis-2-Ac5c-Phe-Val-NH2. The methodology described in this investigation could be applied to a wide variety of peptide systems.
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PMID:Absolute configuration for peptidomimetic residues in bioactive peptides. 174 64

We report the conformational analysis of a series of cyclic hexapeptides related to the hormone somatostatin utilizing 1H NMR spectroscopy and NOE restrained molecular dynamics. The conformational preferences and results from biological analysis of these analogs (previous paper) allow for refinement of the current understanding of the structure-activity relationship of somatostatin. For most of the molecules examined, a beta II' turn about the D-tryptophan-lysine residues, postulated to be required for biological activity, was present. From the NOE restrained molecular dynamics, it can be seen that the turn structure is important for the maintenance of the proper orientation of the side chains of the adjacent phenylalanine, tryptophan and lysine. The biologically active analogs have the side chains of lysine and D-tryptophan extended away from the 18-membered ring in close proximity to each other for a significant portion of the dynamic simulations. Although other conformations are accessible and monitored during the simulations, we believe this is important for biological recognition. The absence of the beta II' turn at the D-tryptophan-lysine disrupts this side chain array producing inactive molecules. The role of the bridging region, the Phe-Pro dipeptide, is to stabilize the beta II' turn and help maintain the proper orientation of the biologically important side chains.
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PMID:Cyclic hexapeptides related to somatostatin. Conformational analysis employing 1H-NMR and molecular dynamics. 198 Apr 90

Cyclic-disulfide-containing analogues of somatostatin, Xaa1-Cys2-Xaa3-DTrp4-Lys6-Thr5-Xaa7- Xaa8 [Xaa1 = H or DPhe; Xaa3 = Phe or Tyr; Xaa7 = Cys, Me2Cys or Me2DCys; Xaa8 = OH, Thr8 (OH) or Thr8NH2], were examined in aqueous solution by 1H-NMR spectroscopy and circular dichroism. The influence of the helical nature of the disulfide bridge and the presence of exocyclic residues on biological activity were investigated with particular care.
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PMID:Conformation of two somatostatin analogues in aqueous solution. Study by NMR methods and circular dichroism. 257 30

A computer program has been developed which allows exhaustive exploration of the conformation of medium sized rings (8 to 22-membered). This program provides for inclusion of experimental data from NMR measurements in the form of dihedral angles estimated by the Karplus equation and NOE close contacts. A brief description of the principles used in the program to provide high efficiency are given as is a discussion of the application of this program to a cyclic hexapeptide somatostatin analogue.
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PMID:Computer-aided, systematic search of peptide conformations constrained by NMR data. 375 67

Effects of peripheral venous injection of glucagon and insulin on [1-13C]glucose incorporation into hepatic glycogen of rats were studied by 13C NMR in vivo. Each animal was given a continuous somatostatin infusion and a 100-mg intravenous injection of [1-13C] glucose in NMR experiments or unlabeled glucose in parallel experiments for determination of serum glucose. Insulin administration caused serum glucose to fall below basal levels and accelerated the loss of hepatic [1-13C]glucose; these effects were counteracted by the addition of glucagon. Glucagon administration alone did not affect serum glucose or hepatic [1-13C] glucose but caused the loss of [1-13C]glucose from glycogen and inhibited [1-13C]glucose incorporation into glycogen. Insulin did not alter [1-13C]glucose incorporation into glycogen when given alone or in combination with glucagon. The data are consistent with a model in which liver glycogen synthesis increases linearly with hepatic glucose concentration above a threshold glucose concentration. Insulin did not alter the rate constant or the threshold for synthesis.
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PMID:Effects of hormone and glucose administration on hepatic glucose and glycogen metabolism in vivo. A 13C NMR study. 390 7

360 MHz 1H-NMR data are presented for somatostatin and an analog whose primary structure is cyclo(-Gaba-Asn5-Phe6-Phe7-DTrp8-Lys9-Thr10-Phe11-). This report focuses on the aromatic portion of the spectrum, and this region for the analog is unambiguously assigned, using two experimental approaches: selective deuteration and photo-induced CIDNP. The most prominent feature of the analog aromatic spectrum is a two-proton resonance which exhibits a pronounced upfield shift. Significantly, this feature is also present for somatostatin and other active analogs (unpublished data). Assignments show that this resonance derives from the ortho hydrogens of the Phe6 and that aromatic resonances of Phe6 shift markedly upfield as temperature is decreased. In contrast, the aromatic resonances of Phe7,11 and DTrp8 reveal generally much smaller temperature coefficients and shift primarily downfield as temperature is decreased. Ring-current analysis shows that simple pair-wise parallel pi-stacking alone cannot give rise to the observed data. However, a simple hypothesis involving only two phenylalanine residues is totally consistent with the data if they maintain a time-averaged co-perpendicular orientation. Indirect evidence is offered which implicates only one phenylalanine stacking partner for Phe6, which we tentatively identify as Phe11.
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PMID:High-field 1H NMR studies of synthetic analogs of somatostatin. Structural features involving aromatic residues in an active eight-membered ring analog. 612 4

The results of a conformational study by 1H and 13C high-resolution NMR at 270 and 500 MHz on the peptide hormone somatostatin have been compared with a series of conformers generated by semi-empirical energy calculations. The use of specifically deuterated phenylalanine residues has enabled us to confirm and supplement the identification of all but the phenylalanine aromatic resonances in the proton spectra of somatostatin. In order to minimize the risk of overlooking some low-energy conformations, four different strategies have been used for the generation of the conformers: two based on combinations of conformations of fragments that had been studied before, one on a random procedure and one on the conformational constraints existing in bicyclic analogs with high biological activity. The experimental values of 3JNH-C alpha H and 3J alpha beta coupling constants and the existence of several ring current shifts allowed us to select from the calculations those families of low-energy conformers that are compatible with the NMR results. The NH temperature coefficients do not warrant the existence of any stable beta or gamma turns in the molecule, although the region SRIF8-12 seems to be the most stable in this respect. In addition there are several upfield shifts: 0.2-0.4 ppm on the Lys9 side-chain, 0.3-0.5 ppm on the Phe6 alpha, beta and Phe7 alpha protons, as well as some 0.2-0.3 ppm shifts on parts of two phenylalanine ring systems. Almost all of these shifts decrease considerably with increasing temperature. Most of the observed NMR results are compatible with the properties of one family of low-energy conformations whose main features are a double beta II bend Trp8-Lys9, Thr10 -Phe11, a close proximity of the Trp8 and Lys9 side chains and an orientation of Phe7 towards the Phe6 alpha, beta protons. We conclude that this set of conformations forms a major contribution to the conformational equilibrium at room temperature. The properties of this and several other sets of low-energy conformations that do not dominate in aqueous solution are discussed in relation to al available experimental evidence.
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PMID:The conformational properties of somatostatin. IV. The conformers contributing to the conformation equilibrium of somatostatin in aqueous solution as found by semi-empirical energy calculations and high-resolution NMR experiments. 612 6


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