Interaction of Amino Acid Residues at Positions 8–15 of Secretin with the N‐Terminal Domain of the Secretin Receptor

Gourlet, Philippe; Vilardaga, Jean‐Pierre; Neef, Philippe De; Vandermeers, André; Waelbroeck, Magalì; Bollen, Alex; Robberecht, Patrick

doi:10.1111/j.1432-1033.1996.0349u.x

Cited by 36 publications

(29 citation statements)

References 38 publications

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“…Theoretical predictions of conformation have suggested the possibility that a coiled-coil interaction might exist between extended ␣-helices in ligands and in the distal amino-terminal tail domain of receptors in this family (32). The critical importance of this region has also been experimentally supported by receptor truncation, site-directed mutagenesis, and chimeric receptor studies (9,(33)(34)(35)(36)(37)(38). Affinity labeling studies have provided direct experimental data to support this interpretation.…”

Section: Discussionmentioning

confidence: 61%

“…8). In three independent experiments, the peak in eluted radioactivity appeared consistently in cycle 3, corresponding to the covalent labeling of receptor residue Leu 36 . Identical results were observed when sequencing the labeled fragment purified after CNBr cleavage and subsequent Lys-C cleavage (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Further confirmation of the identity of the covalently labeled residue as Leu 36 came from biosynthetic labeling studies. In these, [ 3 H]Leu was incorporated into newly synthesized proteins in the SecR-HA37-expressing CHO cell line.…”

Section: Resultsmentioning

confidence: 99%

“…This probe was a full agonist that bound to its receptor with high affinity. Like the Bpa 22 probe, this probe labeled a residue within the amino-terminal tail of the receptor, in position Leu 36 .…”

Section: Discussionmentioning

confidence: 99%

“…Shown is the radioactivity elution profile from sequencing of the Lys-C fragment of the deglycosylated secretin receptor labeled with the Bpa 26 probe. In three independent experiments, the peak in radioactivity consistently appeared in elution cycle 3, representing receptor residue Leu 36 . WT, wild type; a.a., amino acid.…”

Section: Figmentioning

confidence: 99%

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Identification of Two Pairs of Spatially Approximated Residues within the Carboxyl Terminus of Secretin and Its Receptor

Dong

Asmann

Zang

et al. 2000

Journal of Biological Chemistry

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The carboxyl-terminal domains of secretin family peptides have been shown to contain key determinants for high affinity binding to their receptors. In this work, we have examined the interaction between carboxyl-terminal residues within secretin and the prototypic secretin receptor. We previously utilized photoaffinity labeling to demonstrate spatial approximation between secretin residue 22 and the receptor domain that includes the first 30 residues of the amino terminus (Dong, Detailed understanding of the molecular basis of ligand binding and receptor activation will be the key to facilitate the rational design of new drugs. Guanine nucleotide-binding protein (G protein)-coupled receptors represent the largest group of plasma membrane receptors and include many potentially important targets for therapeutic agents, making this superfamily an ideal focus for these efforts.MThis superfamily includes receptor families that share sequence homologies and structural similarities of their natural ligands. Among these is the recently described class II family that includes receptors for secretin, calcitonin, parathyroid hormone, glucagon, vasoactive intestinal polypeptide, and pituitary adenylate cyclase-activating polypeptide (3, 4). The natural agonist ligands of these receptors have helical domains in both carboxyl-terminal and amino-terminal regions (5, 6) and have binding determinants that are spread throughout their entire length (3, 4, 7). The theme is emerging that aminoterminal regions of these peptides contain key determinants for receptor selectivity, whereas carboxyl-terminal regions contain determinants for high affinity binding (8, 9). Of note, the carboxyl-terminal regions of some of the members of this family may even be interchanged while maintaining high affinity binding (9). This feature supports the likely general relevance of the observations in the current work to the entire class II family.We recently used affinity labeling to demonstrate spatial approximation between a photolabile residue within the carboxyl-terminal half of secretin (position 22) and a 30-residue segment at the distal amino terminus of its prototypic secretin receptor (1). Of interest, the amino-terminal tail of the class II G protein-coupled receptor family has remarkable structural features and major functional importance (3,4). This receptor domain is moderately large, containing greater than 110 residues, with six conserved Cys residues and key disulfide bonds (10). Chemical reduction and treatment with sulfhydryl-reactive compounds have had substantial negative impact on these receptors (10 -12). Truncation, site-directed mutagenesis, and chimeric receptor studies have also supported the critical role of this domain in the function of this receptor family (9,13).In the present work, we have extended our understanding of the siting of secretin residue 22 when bound to its receptor by defining a receptor residue adjacent to it. We have also established spatial approximation between another residue closer to the carboxyl ter...

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Section: Discussionmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

See 3 more Smart Citations

Identification of Two Pairs of Spatially Approximated Residues within the Carboxyl Terminus of Secretin and Its Receptor

Dong

Asmann

Zang

et al. 2000

Journal of Biological Chemistry

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Photoaffinity scanning in the mapping of the peptide receptor interface of class II G protein—coupled receptors

Pham

Sexton

2003

Journal of Peptide Science

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The family of G protein-coupled receptors constitutes about 50% of the therapeutic drug targets used in clinical medicine today, although the mechanisms of ligand binding, activation and signal transduction for G protein-coupled receptors are not yet well defined. This review discusses ongoing research using the photoaffinity scanning method to map the bimolecular interface between class II G protein-coupled receptors and their ligands. Furthermore the available computer model of class II peptide ligand docking into the receptor, based on the positional constraints imposed by the photoaffinity scanning analyses, will be discussed briefly. The ultimate goal of these efforts is to understand the molecular basis of receptor binding and therefore to generate a template for rational drug design.

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Secretin-Mediated Gene Delivery, a Specific Targeting Mechanism with Potential for Treatment of Biliary and Pancreatic Disease in Cystic Fibrosis

McKay¹,

Reynolds²,

Jezzard³

et al. 2002

Molecular Therapy

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Gene therapy directed to the gastroenterological manifestations of cystic fibrosis (CF) would ideally be administered systemically. Such delivery would require efficient targeting at the cellular level to achieve a safe and effective therapy. Here we describe gene delivery using the secretin receptor (SR) as a basolateral target specific to the biliary and pancreatic epithelia affected in CF patients. We describe here targeting of a polycation-based nonviral gene delivery vector and retargeting of an adenoviral vector to cells expressing the SR in vitro. We were able to transfect cells expressing the SR up to 10-fold more efficiently than those not expressing the SR with a targeted polycation, SecGGC-lPEI. This targeting effect was secretin-specific and substantially reduced by competing secretin. SR-retargeted adenovirus transduced SR-expressing cells at more than sixfold higher levels than adenovirus alone. The SR may be an effective target for targeting systemically applied viral and nonviral gene delivery constructs to disease-affected tissues in CF patients.

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Interaction of Amino Acid Residues at Positions 8–15 of Secretin with the N‐Terminal Domain of the Secretin Receptor

Cited by 36 publications

References 38 publications

Identification of Two Pairs of Spatially Approximated Residues within the Carboxyl Terminus of Secretin and Its Receptor

Identification of Two Pairs of Spatially Approximated Residues within the Carboxyl Terminus of Secretin and Its Receptor

Photoaffinity scanning in the mapping of the peptide receptor interface of class II G protein—coupled receptors

Secretin-Mediated Gene Delivery, a Specific Targeting Mechanism with Potential for Treatment of Biliary and Pancreatic Disease in Cystic Fibrosis

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