The N-Formyl Peptide Receptor

Mills, John; Miettinen, Heini M.; Vlases, Michael J.; Jesaitis, Algirdas J.

doi:10.1007/978-1-59259-253-1_10

Cited by 10 publications

(6 citation statements)

References 213 publications

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“…In this regard, 3-D modeling of the dimensions and spatial volumes for retinal, fMLP and LXA 4 have shown that they are remarkably similar in the 3-D spatial volumes [58]. Hence, similarities among the 3-D spatial volumes of ligands should reflect complementary sites in respective receptors as well as illustrate the spatial 3-D similarities among peptide vs. non-peptide or even lipid mediator ligands that might otherwise not seem obvious from their chemical structures.…”

Section: Pro-resolving Gpcrsmentioning

confidence: 99%

Novel Anti-Inflammatory-Pro-Resolving Mediators and Their Receptors

Serhan¹,

Krishnamoorthy²,

Recchiuti³

et al. 2011

CTMC

240

200

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Resolution of inflammation, an actively coordinated program, is essential to maintain host health. It involves effective removal of inflammatory stimuli and the spatio-temporal control of leukocyte trafficking as well as chemical mediator generation. During the active resolution process, new classes of small, local acting endogenous autacoids, namely the lipoxins, D and E series resolvins, (neuro)protectins, and maresins have been identified. These specialized pro-resolving lipid mediators (SPM) prevent excessive inflammation and promote removal of microbes and apoptotic cells, thereby expediting resolution and return to tissue homeostasis. As part of their molecular mechanism, SPM exert their potent actions via activating specific pro-resolving G-protein coupled receptors. Together these SPM and their receptors provide new concepts and opportunities for therapeutics, namely promoting active resolution as opposed to the conventionally used enzyme inhibitors and receptor antagonists. This approach may offer new targets suitable for drug design for treating inflammation related diseases, for the new terrain of resolution pharmacology.

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Section: Pro-resolving Gpcrsmentioning

confidence: 99%

Novel Anti-Inflammatory-Pro-Resolving Mediators and Their Receptors

Serhan¹,

Krishnamoorthy²,

Recchiuti³

et al. 2011

CTMC

240

200

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“…Roles for Arg-201 and Arg-205 in FPR Function-Modeling of FPR suggests that both Arg-201 and Arg-205 are located sufficiently close to Asp-106 that either one of them might form an ion pair with Asp-106 (30). A direct interaction between helix III and helix V in FPR would be similar to what has been shown for rhodopsin, where Glu-122 (III-12) in helix III was shown to directly interact with His-211 (V-10) of helix V using Fourier transform infrared spectroscopy (31).…”

Section: D106n Fpr Mutant Localizes Nhmentioning

confidence: 99%

“…Carboxyl Modifications of fMLF Suggest Arg-205 Interacts with the Carboxyl Terminus of fMLF-Since analog analysis on the C5a receptor and the angiotensin I receptor indicate that position 6 of the fifth transmembrane-spanning region is the likely interaction site between the COOH-terminal carboxylate of these peptide ligands and their respective receptors (30,31), we attempted to ascertain whether Arg-205 (V-6) of FPR might interact with the COOH terminus of fMLF. We therefore synthesized several COOH-terminal analogs of fMLF and tested wt FPR, D106N, R201A, and R205A for their ability to bind these analogs.…”

Section: Identification Of Formyl Binding Site In Fprmentioning

confidence: 99%

“…mediated via a water molecule bound to the retinal Schiff base (35)(36)(37)(38). In addition, Glu-122 (III-12) of rhodopsin interacts with His-211 (V-10) (30,38). FPR Asp-106 at position eight of helix III is midway between these two ion-pairing residues, but one would expect FPR Asp-106 to be more closely aligned with rhodopsin Glu-122 (⌬ is 4 residues for Glu-122 or 400°rotation versus 5 residues or 500°for Glu-113).…”

Section: D106n and R201a Bind A Peptide Derived From Hiv (Dp178) Morementioning

confidence: 99%

“…Clearly, the newly discovered promiscuity of FPR for MMWLL and DP-178 suggests the existence of multiple binding locations, one of which might still be compatible with our original retinal in rhodopsin-like placement of fMLF. Clearly, fMMWLL, fNle-Leu-Phe-Nle-Tyr-Lys-fluorescein, and other chemotactic peptides that are longer than three amino acids would not have a free carboxyl group in position three, and might take on a kinked conformation which might enable it to take advantage of the hydrophobic nature of the space between helices II and VII (30).…”

Section: D106n and R201a Bind A Peptide Derived From Hiv (Dp178) Morementioning

confidence: 99%

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Characterization of the Binding Site on the Formyl Peptide Receptor Using Three Receptor Mutants and Analogs of Met-Leu-Phe and Met-Met-Trp-Leu-Leu

Mills

Miettinen

Cummings

et al. 2000

Journal of Biological Chemistry

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The formyl peptide receptor (FPR) 1 is a chemoattractant G protein-coupled receptor found on the surface of phagocytes. It is thought to play an important role in allowing phagocytic cells to recognize the presence of bacteria (1), which are a source of formyl peptides (2, 3). In addition, it recognizes and is activated by peptides derived from the GP-41 envelope protein of the human immunodeficiency virus type I (HIV-1) (4, 5). Recent studies with FPR-deficient mice indicate that they exhibit an increased susceptibility to infection with Listeria monocytogenes and that neutrophils from these knockout mice fail to exhibit chemotaxis in response to fMLF (6).The formyl peptide receptor was originally identified based on its ability to bind the formylated peptide, fMLF (1). Six different chemotactic peptides have been isolated from Escherichia coli, including fMLF (3), but the only similarity between them was an NH 2 -terminal formyl methionine, suggesting that this moiety is highly important in binding to FPR. Studies using NH 2 -terminal analogs of MLF had indicated that the formyl group had significant effects on the ligand binding affinity for neutrophil FPR. Free amino, desamino, and acetylated derivatives of MLF were all 3000-fold lower in affinity than fMLF (7). Substitution of the formyl group of fMLF with a tert-butyloxycarbonyl group made the ligand an antagonist of low affinity (8). However, the formyl group may be less essential than originally thought. N-Butyloxycarbonyl MLF exhibits agonist activity (9) with an affinity similar to fMLF, and phenyl and tolyl isourea derivatives of MLF exhibit activity similar to or greater than fMLF (10). On the other hand, most aliphatic isourea derivatives of MLF exhibit low affinity antagonist activity similar to what is observed with tert-butyloxycarbonyl-MLF (10). This difference indicates that FPR exhibits a high degree of specificity for NH 2 -terminal modifications of MLF, and that the specificity for the formyl group is not absolute. In addition, other reports have indicated that non-formylated pentapeptides can activate FPR. Both MNleLFF and MMWLL are effective activators of FPR (11,12), and acetyl-MNleLFF is more potent than fMLF (12), indicating that these pentapeptides exhibit somewhat different NH 2 -terminal specificities than does MLF.We have previously shown that the formyl peptide binding site maps to several membrane-spanning regions (13-14). Ten residues which affect fMLF binding have been mapped to transmembrane domains II-VII (13), including residues Leu-78 (II-17, helix II, residue 17 of 26 transmembrane-spanning residues in the nomenclature used throughout this text), Asp-106 (III-8), Leu-109 (III-11), Thr-157 (IV-18), Arg-201 (V-2), Ile-204 (V-5), , , and Phe-291 (VII-11). In addition, photo-cross-linking data suggest that the leucine side chain of fMLF is probably located close to FPR 93 VRK 95 , which is at the COOH terminus of helix II (14).Human FPR is one of three receptors in the human FPR family, which includes, FPR, the lipoxin A 4 re...

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Synthesis and Pharmacological Evaluation of New Pyridazin‐Based Thioderivatives as Formyl Peptide Receptor (FPR) Agonists

Crocetti¹,

Vergelli²,

Cilibrizzi³

et al. 2013

Drug Development Research

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A new series of pyridazinone-based thioderivatives and pyridazine analogs was synthesized and tested for their ability to bind to the three human formyl peptide receptor (FPR) isoforms (FPR1, FPR2, and FPR3) and to activate intracellular calcium mobilization and chemotaxis in human neutrophils. Among the pyridazin-3(2H)-one derivatives tested, analogs 8b and 8c were mixed FPR1/FPR2 agonists, with median effective concentration values in the micromolar range, and were able to activate chemotaxis and Ca 2+ flux in human neutrophils in the low micromolar range. Molecular docking studies showed that interaction of a ligand with Arg205 of FPR1 is important for FPR1 agonist activity. For FPR2, differences in activity between oxygen-containing compounds and their thio-analogs were due to steric bulkiness of sulfur-containing groups. Drug Dev Res 74 : 259-271, 2013.

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The N-Formyl Peptide Receptor

Cited by 10 publications

References 213 publications

Novel Anti-Inflammatory-Pro-Resolving Mediators and Their Receptors

Novel Anti-Inflammatory-Pro-Resolving Mediators and Their Receptors

Characterization of the Binding Site on the Formyl Peptide Receptor Using Three Receptor Mutants and Analogs of Met-Leu-Phe and Met-Met-Trp-Leu-Leu

Synthesis and Pharmacological Evaluation of New Pyridazin‐Based Thioderivatives as Formyl Peptide Receptor (FPR) Agonists

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