Natural peptide analgesics: the role of solution conformation

Spadaccini, Roberta; Temussi, Piero Andrea

doi:10.1007/pl00000797

Cited by 34 publications

(42 citation statements)

References 91 publications

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“…NOESY spectra of enkephalin in bulk water, in the temperature range 273^293 K (Fig. 2a), show practically no cross peaks, as expected from literature data [14], whereas the spectrum in aqueous solution inside the gel is similar to the corresponding one in the cryomixture (Fig. 2b).…”

Section: Resultssupporting

confidence: 82%

NMR studies of flexible peptides in cavities mimicking the synaptic cleft

et al. 2002

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The interaction of neuropeptides with post-synaptic receptors is characterised by a high entropic barrier originating from the combination of nanomolar concentration with low conformer population. The influence of high viscosity environments on conformer distribution can help overcome this difficulty. In an attempt to simulate the physicochemical conditions of the synaptic cleft, 15 N-labelled enkephalin has been studied in polyacrylamide gels swollen by different aqueous solutions in the temperature range 273^293 K. Nuclear Overhauser enhancement spectra in the gel pores are consistent with a conformational selection or a slowing down of internal motions that can favour the interaction of the peptide with the receptor. ß

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Section: Resultssupporting

confidence: 82%

NMR studies of flexible peptides in cavities mimicking the synaptic cleft

et al. 2002

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“…As with many peptides studied by NMR (20,42) the TM IV segment does not, as a whole, assume a single conformation. Rather, sections within the peptide converge structurally.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Characterization of Transmembrane Segment IV of the NHE1 Isoform of the Na+/H+ Exchanger

Slepkov¹,

Rainey

Li³

et al. 2005

Journal of Biological Chemistry

150

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The Na ؉ /H ؉ exchanger isoform 1 is a ubiquitously expressed integral membrane protein that regulates intracellular pH in mammals. We characterized the structural and functional aspects of the critical transmembrane (TM) segment IV. Each residue was mutated to cysteine in cysteineless NHE1. TM IV was exquisitely sensitive to mutation with 10 of 23 mutations causing greatly reduced expression and/or activity. The Phe 161 3 Cys mutant was inhibited by treatment with the water-soluble sulfhydryl-reactive compounds [2-(trimethylammonium)ethyl]methanethiosulfonate and [2-sulfonatoethyl]methanethiosulfonate, suggesting it is a pore-lining residue. The structure of purified TM IV peptide was determined using high resolution NMR in a CD 3 OH:CDCl 3 :H 2 O mixture and in Me 2 SO. In CD 3 OH: CDCl 3 :H 2 O, TM IV was structured but not as a canonical ␣-helix. Residues Asp 159 -Leu 162 were a series of ␤-turns; residues Leu 165 -Pro 168 showed an extended structure, and residues Ile 169 -Phe 176 were helical in character. These three structured regions rotated quite freely with respect to the others. In Me 2 SO, the structure was much less defined. Our results demonstrate that TM IV is an unusually structured transmembrane segment that is exquisitely sensitive to mutagenesis and that Phe 161 is a pore-lining residue.

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“…There are also amidated tetrapeptides like endomorphins, which are structurally unrelated to the typical opioid peptides, but show highest affinity and selectivity for the MOP-R [122]. Structural studies of several opioid peptides in different solvents have been reported [24,25,123]. A recent article discusses conformational analysis of opioid peptides in the solid states and the membrane environments [124].…”

Section: Opioid Peptidesmentioning

confidence: 96%

Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

Sankararamakrishnan

2006

Bioscience Reports

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One of the largest family of cell surface proteins, G-protein coupled receptors (GPCRs) regulate virtually all known physiological processes in mammals. With seven transmembrane segments, they respond to diverse range of extracellular stimuli and represent a major class of drug targets. Peptidergic GPCRs use endogenous peptides as ligands. To understand the mechanism of GPCR activation and rational drug design, knowledge of threedimensional structure of receptor-ligand complex is important. The endogenous peptide hormones are often short, flexible and completely disordered in aqueous solution. According to ''Membrane Compartments Theory'', the flexible peptide binds to the membrane in the first step before it recognizes its receptor and the membrane-induced conformation is postulated to bind to the receptor in the second step. Structures of several peptide hormones have been determined in membrane-mimetic medium. In these studies, micelles, reverse micelles and bicelles have been used to mimic the cell membrane environment. Recently, conformations of two peptide hormones have also been studied in receptor-bound form. Membrane environment induces stable secondary structures in flexible peptide ligands and membrane-induced peptide structures have been correlated with their bioactivity. Results of site-directed mutagenesis, spectroscopy and other experimental studies along with the conformations determined in membrane medium have been used to interpret the role of individual residues in the peptide ligand. Structural differences of membrane-bound peptides that belong to the same family but differ in selectivity are likely to explain the mechanism of receptor selectivity and specificity of the ligands. Knowledge of peptide 3D structures in membrane environment has potential applications in rational drug design.

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Natural peptide analgesics: the role of solution conformation

Cited by 34 publications

References 91 publications

NMR studies of flexible peptides in cavities mimicking the synaptic cleft

NMR studies of flexible peptides in cavities mimicking the synaptic cleft

Structural and Functional Characterization of Transmembrane Segment IV of the NHE1 Isoform of the Na+/H+ Exchanger

Recognition of GPCRs by Peptide Ligands and Membrane Compartments theory: Structural Studies of Endogenous Peptide Hormones in Membrane Environment

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