Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The conformation of cyclo-[Gln-Trp-Phe-Gly-Leu-Met], a potent tachykinin antagonist selective for the NK-2 receptor, has been studied by 1H NMR spectroscopy in DMSO-d6 and in a DMSO-d6/H2O cryoprotective mixture in the temperature range 280-320 K. The NMR data cannot be interpreted on the basis of a single ordered conformation. An exhaustive search, based mainly on missing NOEs among skeleton protons, yields a description of the conformational state in solution consisting of a few interconverting structures that can explain all observed NMR parameters. The relative position of the side chains of key residues may be interpreted in terms of bioactive conformations.
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PMID:Solution conformation of c-[Gln-Trp-Phe-Gly-Leu-Met], a NK-2 tachykinin antagonist. 770 77

The S/T-X1-X2-N-P-X3-X4-Y highly conserved sequence of the seventh transmembrane (TM VII) segment of G-protein-coupled receptors is not present in the photon receptor bacteriorhodopsin TM VII domain. Despite this noticeable discrepancy in sequence, the X-ray structure of bacteriorhodopsin is generally used as the key structure for modelling all G-protein-coupled receptors. Thus, a kinked trans Pro-helix is usually accepted for the TM VII three-dimensional structure of G-protein-coupled receptors, although Asn-Pro dipeptide mainly induces a type I/III beta-turn conformation in both model peptides and proteins. NMR studies in various solvents and molecular calculations were undertaken in order to gain insight into the conformational behaviour of a 15-residue peptide from the tachykinin NK-1 TM VII domain incorporating this common sequence. The low solubility of this membrane-embedded peptide precludes methanol or micellar systems mimicking membrane environment; thus only dimethylsulfoxide (Me2SO) or chloroform/Me2SO mixture could be used. We also found that perfluoro-tert-butanol, which has not been previously used for NMR studies, constitutes an excellent alternative solvent for the analysis of hydrophobic peptides. The postulated kinked trans-Pro helix was only present as a minor conformer in Me2SO and an equilibrium between helical and extended structures existed. From NOE data a type I/III beta-structure, centered around Pro9-Ile10, probably stabilized by an Asx turn, may be postulated. Addition of chloroform in Me2SO increased the percentage of folded structures but no preferential conformation could be proposed. In perfluoro-tert-butanol/CD3OD (9:1) the N- and C-terminal regions presented an alpha-helical structure, and these two domains were linked by a hinge around Asn-Pro with a gamma-turn for the preceding residue Tyr7 and either a type I/III beta-turn around Pro9-Ile10 or alpha R orientations for these residues, which are both stabilized by an Asx turn. As determined by energy calculations, these structures were equally as stable as the kinked trans-Pro helix and could constitute key structures for analysing the conformational changes and/or the dynamics of TM VII segment induced by the ligand when interacting with the receptor.
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PMID:Three-dimensional structure of the highly conserved seventh transmembrane domain of G-protein-coupled receptors. 795 20

The nonmammalian tachykinin eledoisin was investigated by use of CD and two-dimensional NMR techniques. In aqueous solution the peptide is conformationally averaged, but on addition of 50% trifluoroethanol (TFE) or sodium dodecyl sulfate (SDS) it adopts an alpha-helical structure. In TFE/H2O and SDS, residues 6-10 of eledoisin show more conformational order than the terminal regions, which undergo dynamic fraying. A possible turn in the N-terminal "address" region, the putative receptor recognition site of the peptide, is detected by NMR spectroscopy but appears to undergo substantial conformational averaging. The NMR data indicate that the helical central core of eledoisin is better defined in the micellar environment than in TFE; however, partial unfolding via 3(10) intermediates occurs in both cases. The conformational preference for SDS-bound eledoisin was examined by three-dimensional structure calculations using NMR-derived distance information in simulated annealing calculations.
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PMID:A determination of the solution conformation of the nonmammalian tachykinin eledoisin by NMR and CD spectroscopy. 820 14

1H NMR chemical shift assignments for neuropeptide K (NPK) and neurokinin A (NKA) have been determined at 600 MHz in 28% trifluoroethanol/water solution. Two-dimensional NMR techniques were used to assign proton resonances, and interproton distances were estimated from the observed nuclear Overhauser effects (NOEs). These distances were used as constraints in a simulated annealing protocol within the program XPLOR to generate structures consistent with experimental data. NPK forms a regular amphipathic alpha-helical structure from Asp 3, terminating at Gly 18. Slowly exchanging amide protons identified in this region are likely to be involved in hydrogen bonds to stabilize the helix. The remainder of the molecule displays many sequential NOEs, with some i-(i + 2) contacts, but little further evidence of defined secondary conformation. NKA displays strong sequential connectivities between amide protons from Thr 3 to Met 10, and some i-(i + 2) connectivities suggestive of a series of dynamic turns in equilibrium. A comparison of the tail region of NPK with the related peptide homologue, neurokinin A, in the same solvent system, indicates that both show increasing order when trifluoroethanol is titrated into water solution, with the appearance of sequential NOEs between backbone amide protons. Differences between the corresponding spans of primary sequence appear to be minimal. The clear finding that NPK adopts a well-defined helix in its N-terminal half and is relatively disordered in the C-terminal half, which includes the entire NKA sequence, may have important implications for understanding the increased selectivity of NPK over NKA for one class of neurokinin receptor.
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PMID:Determination of the solution structure of neuropeptide K by high-resolution nuclear magnetic resonance spectroscopy. 839 41

The application of the concept of backbone cyclization to linear substance P (SP) analogs is presented. We describe the synthesis, characterization, and biological activity of a series of backbone-to-amino-terminus cyclic analogs of the C-terminal hexapeptide of SP. These analogs were designed on the basis of NMR data and molecular modeling of the selective NK-1 analog WS-septide (Ac[Arg6,Pro9]SP6-11). A series of peptides with the general formula: cyclo[-CH2)m-NH-CO-(CH2)n-CO-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2 (n = 2, 3, 6 and m = 2, 3, 4) was synthesized by solid phase methodology using Fmoc chemistry for the main chain and Boc chemistry for the building units [Na-(omega-aminoalkyl)Gly] side chains. Cyclization was performed on the resin after removal of the Boc protecting group from the omega-aminoalkyl chain. Cyclic and precyclic analogs were compared. They were purified by HPLC and characterized by mass spectroscopy and NMR. Biological activity and selectivity to the NK-1 neurokinin receptor were found to depend on cyclization and the ring size: The most active and selective analog had a ring of 20 atoms. This analog was found to have enhanced metabolic stability in various tissue preparation compared to WS-septide.
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PMID:Synthesis and biological activity of NK-1 selective, N-backbone cyclic analogs of the C-terminal hexapeptide of substance P. 875 39

NMR and CD studies have been used to analyze the model membrane-bound structure of the neuropeptide substance P (RPKPQQFFGLM-NH2, SP), which has previously been proposed as the NK1 receptor active form. Conformations were determined for the SP in the presence of aqueous solutions of zwitterionic dodecylphosphocholine (DPC) and anionic sodium dodecylsulfate (SDS) micelles. The two structures are similar, although fast exchange between free and bound forms was observed for SP with DPC micelles, and predominantly bound characteristics were found for SP in SDS. The addition of 150-200 mM NaCl had no observable effect on the bound conformation in either case. Thus, the structure of SP at a micelle surface is determined largely by hydrophobic forces, and the electrostatic interactions determine the amount of SP that is bound.
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PMID:The conformation of substance P in lipid environments. 878 30

We review the reported data on the design, the conformational features and the pharmacological properties of the bicyclic peptide tachykinin NK2 receptor antagonist MEN 10,627 or cyclo(Met-Asp-Trp-Phe-Dap-Leu)cyclo(2 beta-5 beta). MEN 10,627 possesses a highly constrained structure characterized by two consecutive beta-turns, as confirmed by the almost coincident results of NMR and X-ray analyses. The compound has been efficiently synthesized by solid-phase methodology using either Boc or Fmoc strategies. It is quite stable to metabolic degradation and is endowed with high affinity and selectivity for NK2 receptor expressed in various species. At the hamster NK2 receptor MEN 10,627 is about 30-fold more potent than the nonpeptide NK2 receptor antagonist, SR 48,968, while the converse is true for the rabbit NK2 receptor. MEN 10,627 and SR 48,968 show comparable affinities for the human NK2 receptor. MEN 10,627 produces a long lasting inhibition of the response to the selective NK2 receptor agonist [beta Ala8]NKA(4-10) in the rat urinary bladder in vivo after intravenous, intranasal and intraduodenal administration. Therefore different administration routes are possible for this compound that overcomes the usual drawbacks for the application of peptides as drugs.
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PMID:A review of the design, synthesis and biological activity of the bicyclic hexapeptide tachykinin NK2 antagonist MEN 10627. 887 36

The three-dimensional structure of amyloid beta peptide (25-35), which has neurotoxic activity, in lithium dodecyl sulfate micelles was determined by two-dimensional 1H NMR spectroscopy with simulated annealing calculations. A total of 20 converged amyloid beta peptide structures were obtained on the basis of 110 experimental constraints, including 106 distance constraints reduced from the nuclear Overhauser effect (NOE) connectivities and four torsion angle (phi) constraints. The atomic root mean square difference about averaged coordinates is 1.04 +/- 0.25 A for the backbone atoms (N, C alpha, C) and 1.39 +/- 0.27 A for all heavy atoms of the entire peptide. The molecular structure of amyloid beta peptide in membrane-mimicking environment is composed of a short alpha helix in the C terminal position. The three residues from the N-terminus are disordered, but the remaining eight C-terminal residues are well-ordered, which is supported by the RMSD values of the C-terminal region, Lys28-Leu34. In this region, the RMS differences from averaged coordinates are 0.26 +/- 0.11 A for the backbone atoms (N, C alpha, C) and 0.77 +/- 0.21 A for all heavy atoms, which is very low compared with those for the entire peptide. The four amino acid residues from the N-terminus are hydrophilic and the other seven amino acid residues in C-terminus are hydrophobic. So, our results show that the C-terminal region of amyloid beta peptide (25-35) is buried in the membrane and assumes alpha-helical structure, whereas the N-terminal region is exposed to the solvent with a flexible structure. This structure is very similar to membrane-mediated structure of substance P previously reported. The three-dimensional structure of a non-neurotoxic mutant of amyloid beta peptide (25-35), where Asn27 is replaced by Ala, in lithium dodecyl sulfate micelles was also determined. The structure is similar to that of the wild type amyloid beta peptide (25-35) in the C-terminal region, but the N-terminal flexible region is different. The structural comparison of amyloid beta peptide (25-35), its non-neurotoxic mutant and substance P gives a structural basis to understand the mechanism of neurotoxicity caused by amyloid beta peptide.
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PMID:Three-dimensional structures of the amyloid beta peptide (25-35) in membrane-mimicking environment. 897 80

The conformations of two backbone-cyclized substance P analogs were derived from homo- and heteronuclear NMR measurements and molecular dynamics simulations carried out in DMSO. The analogs contain subtle variations in the ring chemistry and are compared with biologically active analogs previously examined. The correlation between conformation and activity is used to gain insight into the conformational requirements from the pharmacophore.
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PMID:Structure-activity relationship of the ring portion in backbone-cyclic C-terminal hexapeptide analogs of substance P. NMR and molecular dynamics. 898 90

Both the aqueous and the lipid-induced structure of a representative and widely studied tachykinin, substance P, has been investigated by two-dimensional proton nuclear magnetic resonance (2D 1H-NMR) spectroscopy and distance geometry calculations. Unambiguous NMR assignments of protons have been made with the aid of correlation spectroscopy (COSY and TOCSY) experiments and Overhauser enhancement spectroscopy (ROESY and NOESY; experiments. The NMR data obtained were utilized in a distance geometry algorithm to generate a family of structures which were further refined using restrained energy minimization. These data show that, while in water substance P appears to favour an extended chain conformation, in the presence of perdeuterated dodecylphosphocholine (DPC) micelles as membrane model system an amphiphilic helical conformation is induced in the mid-region (Q5-Q8) of substance P. The conformation adopted by substance P in the presence of DPC micelles yields a structural motif typical of neurokinin-1 selective ligands, as proposed by Convert and coworkers (O. Convert et al., Neuropeptides 19, 259-270 (1991)).
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PMID:Lipid-induced conformation of substance P. 928 76


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