The significance of functional receptor heterogeneity in the biological responses of the rabbit neutrophil to stimulation by chemotactic formyl peptides

Kermode, John C.; Freer, Richard J.; Becker, Elmer L.

doi:10.1042/bj2760715

Cited by 8 publications

(4 citation statements)

References 57 publications

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“…32(2) A of the Cg-Cg bond is in agreement with the average value of 1.323 ( 2) A quoted for this bond.' The planarity imposed by the cr,&double bond should promote an electronic delocalization with shrinking of the C "-N and C"-C' bonds, and lengthening of the carbonyl double bond.…”

supporting

confidence: 90%

Synthesis, conformation, and activity of HCO‐Met‐Δ^Z Leu‐Phe‐Ome, an active analogue of chemotactic N‐formyltripeptides

et al. 1993

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In order to induce a beta-turn conformation into the chemotactic linear tripeptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), the new analogue N-formyl-L-methionyl-delta Z leucyl-L-phenylalanine methyl ester [delta Z Leu]2fMLP-OMe (1) has been synthesized. The conformational and biochemical consequences of this chemical modification have been determined. Analogue 1 has been synthesized by using N-carboxy-(Z)-alpha,beta-didehydroleucine anhydride as key compound to introduce the unsaturated residue at the central position of the tripeptide 1. The x-ray analysis shows that 1 adopts in the crystal a type II beta-turn conformation in which the new residue occupies the (i + 2) position, and an intramolecular H bond is formed between the formylic oxygen and the Phe NH. 1H-nmr analysis based on nuclear Overhauser effect measurements suggests that the same folded conformation is preferred in CDCl3 solution; this finding is also supported by molecular dynamics simulation. The biological activity of 1 has been determined on human neutrophils (polymorphonuclear leukocytes) and compared to that shown by fMLP-OMe. Chemotactic activity, granule enzyme release, and superoxide anion production have been determined. Analogue 1 is practically inactive as chemoattractant, highly active in the superoxide generation, and similar to the parent in the lysozyme release. The conformational restriction imposed on the backbone by the presence of the unsaturated residue is discussed in relation with the observed bioselectivity.

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confidence: 90%

Synthesis, conformation, and activity of HCO‐Met‐Δ^Z Leu‐Phe‐Ome, an active analogue of chemotactic N‐formyltripeptides

et al. 1993

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“…Ligands able to select biological responses may not be surprising, since data emerging from the literature indicate that: (a) two isoforms of the human FPR have already been characterized and isolated (19); (b) a model comprising interconvertible states of different receptor affinities on rabbit peritoneal neutrophils has been proposed (20); and (c) distinct signal transduction pathways responsible for the different neutrophil responses have already been found (4, 9, 10).…”

Section: Discussionmentioning

confidence: 99%

An evaluation of fMLP pocket dimensions and features using formyltetrapeptides

Cavicchioni¹,

Varani²,

Niccoli³

et al. 1999

The Journal of Peptide Research

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The formyltetrapeptides for-Met-Leu-Leu-Phe-OMe 1, for-Met-Leu-Aib-Phe-OMe 2, for-Met-Leu-Ac6c-Phe-OMe 3, for-Met-Leu-Pro-Phe-OMe 4, for-Met-Pro-Pro-Phe-OMe 5, for-Met-Aib-Aib-Phe-OMe 6, for-Met-Pro-Aib-Phe-OMe 7 and for-Met-Aib-Pro-Phe-OMe 8 were synthesized and biologically tested on human neutrophils in an attempt to evaluate the specific receptor pocket dimensions and features. Our results indicate that the shift in the Phe residue to the fourth position in these compounds strongly reduces chemotactic response, but is efficacious in triggering superoxide anion production and lysozyme release (order of potency 3 > 2 > 1 > 4 > 6 > 8 > 5 > 7). The potency of the two latter responses correlates well with the affinity data obtained in binding experiments.

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“…Previously reported results indicate that CHO-MLFFK-FL is a more potent ligand than CHO-NLFNYK-FL (31,32,36), the most potent of the four listed above, and thus CHO-MLFFK-FL has the potential of exhibiting faster ligand binding kinetics or slower rate of conversion to the LR x state than CHO-NLFNYK-FL. There are no previously published data regarding the binding or response characteristics of CHO-VLFK-FL; however, studies of N-formyl peptides with valyl in the first position suggest it would be a relatively weak agonist (37).…”

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confidence: 99%

Receptor Binding Kinetics and Cellular Responses of Six N-Formyl Peptide Agonists in Human Neutrophils

et al. 2004

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The goal of this study was to elucidate the relationships between early ligand binding/receptor processing events and cellular responses for the N-formyl peptide receptor system on human neutrophils as a model of a GPCR system in a physiologically relevant context. Binding kinetics of N-formyl-methionyl-leucyl-phenylalanyl-phenylalanyl-lysine-fluorescein and N-formyl-valyl-leucyl-phenylalanyl-lysine-fluorescein to the N-formyl peptide receptor on human neutrophils were characterized and combined with previously published binding data for four other ligands. Binding was best fit by an interconverting two-receptor state model that included a low affinity receptor state that converted to a high affinity state. Response behaviors elicited at 37 degrees C by the six different agonists for the N-formyl peptide receptor were measured. Dose response curves for oxidant production, actin polymerization, and G-protein activation were obtained for each ligand; whereas all ligands showed equal efficacy for all three responses, the ED(50) values varied as much as 7000-fold. The level of agonism and rank order of potencies of ligands for actin and oxidant responses were the same as for the G-protein activation assay, suggesting that the differences in abilities of ligands to mediate responses were determined upstream of G-protein activation at the level of ligand-receptor interactions. The rate constants governing ligand binding and receptor affinity conversion were ligand-dependent. Analysis of the forward and reverse rate constants governing binding to the proposed signaling receptor state showed that it was of a similar energy for all six ligands, suggesting the hypothesis that ligand efficacy is dictated by the energy state of this ligand-receptor complex. However, the interconverting two-receptor state model was not sufficient to predict response potency, suggesting the presence of receptor states not discriminated by the binding data.

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The significance of functional receptor heterogeneity in the biological responses of the rabbit neutrophil to stimulation by chemotactic formyl peptides

Cited by 8 publications

References 57 publications

Synthesis, conformation, and activity of HCO‐Met‐Δ^Z Leu‐Phe‐Ome, an active analogue of chemotactic N‐formyltripeptides

Synthesis, conformation, and activity of HCO‐Met‐Δ^Z Leu‐Phe‐Ome, an active analogue of chemotactic N‐formyltripeptides

An evaluation of fMLP pocket dimensions and features using formyltetrapeptides

Receptor Binding Kinetics and Cellular Responses of Six N-Formyl Peptide Agonists in Human Neutrophils

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The significance of functional receptor heterogeneity in the biological responses of the rabbit neutrophil to stimulation by chemotactic formyl peptides

Cited by 8 publications

References 57 publications

Synthesis, conformation, and activity of HCO‐Met‐ΔZ Leu‐Phe‐Ome, an active analogue of chemotactic N‐formyltripeptides

Synthesis, conformation, and activity of HCO‐Met‐ΔZ Leu‐Phe‐Ome, an active analogue of chemotactic N‐formyltripeptides

An evaluation of fMLP pocket dimensions and features using formyltetrapeptides

Receptor Binding Kinetics and Cellular Responses of Six N-Formyl Peptide Agonists in Human Neutrophils

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Product

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Synthesis, conformation, and activity of HCO‐Met‐Δ^Z Leu‐Phe‐Ome, an active analogue of chemotactic N‐formyltripeptides

Synthesis, conformation, and activity of HCO‐Met‐Δ^Z Leu‐Phe‐Ome, an active analogue of chemotactic N‐formyltripeptides