Solution structure of dynorphin A (1-17): a NMR study in a cryoprotective solvent mixture at 278 K

Spadaccini, Roberta; Crescenzi, Orlando; Picone, Delia; Tancredi, Teodorico; Temussi, Piero Andrea

doi:10.1002/(sici)1099-1387(199907)5:7<306::aid-psc199>3.0.co;2-b

Cited by 21 publications

(28 citation statements)

References 38 publications

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“…Based on the observation that this peptide binds to a separate orphan receptor (ORL1, OP4) and inhibits the antinociceptive effects of morphine and opioid peptides, it was named orphanin FQ or nociceptin (NC). As shown recently [3], a proteinase present in the spinal cord released two major metabolites: NC (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) and NC (1)(2)(3)(4)(5)(6). Their action after i.c.v.…”

Section: Introductionmentioning

confidence: 74%

Solution conformational study of nociceptin and its 1–13 and 1–11 fragments using circular dichroism and two‐dimensional NMR in conjunction with theoretical conformational analysis

Klaudel

Łęgowska

Brzozowski

et al. 2004

Journal of Peptide Science

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Conformational studies of nociceptin (NC-NH2), its fully active fragment, NC(1-13)-NH2, and two significantly less potent fragments, NC(1-13)-OH and NC(1-11)-OH, were conducted in water and TFE solutions by the employment of circular dichroism, and in DMSO-d6 by 2DNMR spectroscopy in conjunction with theoretical conformational analysis. The conformations of all thepeptides studied were calculated taking two approaches. The first assumes multiconformational equilibrium of the peptide studied, which is characterized by a set of conformations (and their statistical weight values)obtained from a global conformational analysis using three methods: the electrostatically driven Monte-Carlo (EDMC) with the ECEPP/3 force field, the simulated annealing (SA) protocols in the AMBER and CHARMM force fields. The second approach incorporates the interproton distance and dihedral angle constraints into the starting conformation. Calculations were performed using the distance geometry and SA protocol in the CHARMM force field implemented in the X-PLOR program. The CD experiments indicated that for the active peptides, hydrophobic solvents induced a significantly higher (compared with those remaining)content order, probably a helical structure. Unfortunately, as a result of the conformational flexibility of thepeptides, the analysis of conformations obtained with both approaches and different force fields did not alllow the selection of any structural elements of the NC peptides that might be connected with their bioactivity. The only common element found in most conformations of the active peptides was a helical character of fragment 8-13, which allowed the side chains of basic amino acid residues to be exposed to the outside of the molecule and probably to interact with the ORL1 receptor.

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Section: Introductionmentioning

confidence: 74%

Solution conformational study of nociceptin and its 1–13 and 1–11 fragments using circular dichroism and two‐dimensional NMR in conjunction with theoretical conformational analysis

Klaudel

Łęgowska

Brzozowski

et al. 2004

Journal of Peptide Science

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“…In aqueous solutions, peptides often exist as a dynamic ensemble of random coil conformers, with specific folds stabilized by organic solvents or micelles (35)(36)(37). Studies of liposome-bound peptides likewise indicate that nonpolar or membrane-like environments stabilize peptide structure (23,24,(38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opioid receptor

O’Connor

White

Doncescu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…However, both dynorphin A and nociceptin have been structurally elusive. In previous biophysical studies, dynorphin A (25) and nociceptin (26) show little tendency to form well defined structures in water and in other polar solvents.…”

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confidence: 86%

The Nociceptin Pharmacophore Site for Opioid Receptor Binding Derived from the NMR Structure and Bioactivity Relationships

Orsini

Nesmelova

Young

et al. 2005

Journal of Biological Chemistry

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Nociceptin, a 17 amino acid opioid-like peptide that has an inhibitory effect on synaptic transmission in the nervous system, is involved in learning, memory, attention, and emotion and is also implicated in the perception of pain and visual, auditory, and olfactory functions. In this study, we investigated the NMR solution structure of nociceptin in membrane-like environments (trifluoroethanol and SDS micelles) and found it to have a relatively stable helix conformation from residues 4 -17 with functionally important N-terminal residues being folded aperidoically on top of the helix. In functional assays for receptor binding and calcium flux, alanine-scanning variants of nociceptin indicated that functionally important residues generally followed helix periodicity, consistent with the NMR structural model. Structure-activity relationships allowed identification of pharmacophore sites that were used in small molecule data base searches, affording hits with demonstrated nociceptin receptor binding affinities.Nociceptin is a 17 amino acid opioid-like peptide that was identified as a natural ligand of the orphan opioid receptor ORL1 (also referred to as OP4) (1). Reinscheid et al. (2) called the same peptide orphanin FQ to signify that it is a ligand for ORL1 with an N-terminal phenylalanine and a C-terminal glutamine. Nociceptin signaling through ORL1 elicits many of the same responses induced by opioid signaling through the opioid receptors. Nociceptin causes inhibition of adenylyl cyclase (1, 2), activation of potassium channels (3-8), inhibition of calcium channels (9 -11), mobilization of intracellular calcium (10), and activation of mitogen-activated protein kinase (12)(13)(14). These effects indicate that, similar to opioids, nociceptin has an inhibitory effect on synaptic transmission in the nervous system, acting to reduce the secretion of neurotransmitters. Consistent with its cellular effects, nociceptin inhibits the release of glutamate (5, 15-17), ␥-Aminobutyric acid (5), acetylcholine (18, 19), tachykinin (20, 21), and noradrenaline (22) neurotransmitters. Based on their distribution in the brain and spinal cord, nociception and its receptor may be involved in a wide range of functions, including learning, memory, attention, and emotion. Nociceptin is also implicated in various sensory processes such as perception of pain, visual, auditory, and olfactory functions.Nociceptin is related to dynorphin A, a peptide 17-mer ligand of the -opioid receptor. Dynorphin A also binds ORL1 but with 100-fold lower affinity than nociceptin (23). Orphanin FQ2 is another biologically active peptide 17-mer processed from the same nociceptin precursor, prenociceptin (1, 2, 24). Fig. 1 shows the amino acid sequences of orphanin FQ2, nociceptin, and dynorphin A. Although nociceptin and dynorphin A are the most homologous of these three peptides (particularly at the N and C termini and being polycationic), there are clear differences in amino acid sequence that should affect conformation and receptor binding as noted abov...

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Solution structure of dynorphin A (1-17): a NMR study in a cryoprotective solvent mixture at 278 K

Cited by 21 publications

References 38 publications

Solution conformational study of nociceptin and its 1–13 and 1–11 fragments using circular dichroism and two‐dimensional NMR in conjunction with theoretical conformational analysis

Solution conformational study of nociceptin and its 1–13 and 1–11 fragments using circular dichroism and two‐dimensional NMR in conjunction with theoretical conformational analysis

NMR structure and dynamics of the agonist dynorphin peptide bound to the human kappa opioid receptor

The Nociceptin Pharmacophore Site for Opioid Receptor Binding Derived from the NMR Structure and Bioactivity Relationships

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