Arginine 336 and Asparagine 333 of the Human Cholecystokinin-A Receptor Binding Site Interact with the Penultimate Aspartic Acid and the C-terminal Amide of Cholecystokinin

Gigoux, Véronique; Escrieut, Chantal; Fehrentz, Jean‐Alain; Silvente-Poirot, Sandrine; Maigret, Bernard; Moröder, Luis; Gully, Danielle; Martinez, Jean; Vaysse, Nicole; Fourmy, Daniel

doi:10.1074/jbc.274.29.20457

Cited by 74 publications

(115 citation statements)

References 51 publications

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…The resulting theoretical positioning of CCK into the CCK1R binding site was experimentally validated by two-dimensional site-directed mutagenesis. By doing so, Met-195-Arg-197, Arg-336, and Asn-333 were shown to belong the CCK1R binding site and to interact with the sulfated tyrosine of CCK, the Asp-8 carboxylate, and the C-terminal amide, respectively (15)(16)(17). The program package (Insight II, Discover, Homology, Biopolymer) from Molecular Simulations Inc. (San Diego, CA) was used for all the calculations.…”

Section: Methodsmentioning

confidence: 99%

“…, located in the second extracellular loop, were then shown to interact with the sulfated tyrosine (15,16). More recently, Arg-336 and Asn-333, at the top of helix VI, were demonstrated to pair with the Asp carboxylate and the Cterminal amide of CCK, respectively (17). The first two identified amino acids of the CCK1R (Trp-39 and Gln-40) contribute weakly to CCK1R affinity for and response to CCK, whereas all others play a more critical role because of their interaction with residues of CCK, which are essential for both binding and biological activity of CCK.…”

Section: Cholecystokinin (Cck)mentioning

confidence: 99%

“…In a first series of experiments, COS-7 cells expressing mutated receptors were assayed for binding of the non-peptide antagonist [ 3 H]SR-27,897. Indeed, binding of this antagonist, unlike that of an agonist, offers the advantage of allowing detection of CCK1R independent of the coupling state to G protein(s), thus yielding accurate expression levels of all mutants (15,17). Ligand binding data are summarized in Table I.…”

Section: Identification Of Candidate Amino Acid Residues Of the Cck1rmentioning

confidence: 99%

See 2 more Smart Citations

The Biologically Crucial C Terminus of Cholecystokinin and the Non-peptide Agonist SR-146,131 Share a Common Binding Site in the Human CCK1 Receptor

Escrieut

Gigoux

Archer

et al. 2002

Journal of Biological Chemistry

Self Cite

105

View full text Add to dashboard Cite

The cholecystokinin (CCK) receptor-1 (CCK1R) is a G protein-coupled receptor, which mediates important central and peripheral cholecystokinin actions. Our aim was to progress in mapping of the CCK1R binding site by identifying residues that interact with the methionine and phenylalanine residues of the C-terminal moiety of CCK because these are crucial for its binding and These new and important insights will serve to better understand the activation process of CCK1R and to design or optimize ligands.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Cholecystokinin (Cck)mentioning

confidence: 99%

Section: Identification Of Candidate Amino Acid Residues Of the Cck1rmentioning

confidence: 99%

See 1 more Smart Citation

The Biologically Crucial C Terminus of Cholecystokinin and the Non-peptide Agonist SR-146,131 Share a Common Binding Site in the Human CCK1 Receptor

Escrieut

Gigoux

Archer

et al. 2002

Journal of Biological Chemistry

Self Cite

105

View full text Add to dashboard Cite

show abstract

“…Extensive site-directed mutagenesis of the CCK receptor has been attempted as well (Silvente-Poirot et al 1998;Gigoux et al 1999;Gouldson et al 2000). (Gouldson et al 2000).…”

Section: Receptor Mutagenesis Studiesmentioning

confidence: 99%

“…This model is distinct from another extensively-discussed model in the literature that has been based exclusively on receptor mutagenesis studies (Kennedy et al 1997;Gigoux et al 1999). It is important to incorporate as many different types of studies and as many independently-derived constraints as possible in developing such a model.…”

Section: Model Of Agonist-occupied Cck Receptormentioning

confidence: 99%

Molecular Basis of Agonist Binding to the Type A Cholecystokinin Receptor

Miller

Lybrand

2002

Pharmacology & Toxicology

View full text Add to dashboard Cite

Abstract:The receptors for cholecystokinin (CCK) peptides are guanine nucleotide-binding protein-coupled receptors in the rhodopsin/b-adrenergic receptor family. The molecular basis of natural ligand binding to the type A CCK receptor has been studied using ligand structure-activity series, receptor mutagenesis, and photoaffinity labeling studies. These have focused attention on the extracellular loop and tail domains, with the most direct insights coming from intrinsic photoaffinity labeling studies. A model of the binding of CCK to this receptor is consistent with all these studies. This model places the carboxyl terminus of CCK adjacent to the amino-terminal tail outside of transmembrane segment 1, the midregion of the peptide adjacent to the third extracellular loop outside of transmembrane segment 7, and includes a chargecharge interaction between peptide residue tyrosine-sulfate 27 and the arginine residue in the second extracellular loop of the receptor in position 197.Understanding of the molecular basis of agonist binding to receptors and their activation is of great interest and importance for the rational design of receptor-active drugs. The type A cholecystokinin (CCK) receptor is a valid drug target, with particular relevance for agonist drugs that might induce satiety and that could have a role in the pharmacotherapy of obesity. Indeed, orally active small molecule drug candidates with agonist activity at this receptor are being developed (Aquino et al. 1996). A more detailed understanding of the conformation of the active complex of CCK receptor occupied by the natural full agonist ligand, CCK, would help to refine such candidates and to develop new candidate drugs.The CCK receptor is a member of the Class I rhodopsin/ b-adrenergic family of guanine nucleotide-binding protein (G protein)-coupled receptors. This molecule was first identified by affinity labeling using a CCK-like probe (Pearson & Miller 1987) and was later purified, partially sequenced, and had its cDNA cloned (Wank et al. 1992). This assignment to this receptor family is based on sequence homology primarily within the transmembrane domains of member receptors. Being a member of the Class I family provides a particular advantage for the CCK receptor, based on the recent successful solution of a high resolution crystal structure of rhodopsin (Palczewski et al. 2000). It is quite likely that there will be substantial similarity between the conformation of transmembrane helices and bundle formation within the membrane of the CCK receptor and rhodopsin. However, in a recent report, it was demonstrated that the loop and tail positions in rhodopsin are not rel- evant to analogous portions of the CCK receptor (Ding et al. 2002). Homology modeling of the CCK receptor for these regions of rhodopsin yield no binding cleft of adequate size and reasonable position to accommodate the natural peptide ligand. Ligand structure-activity seriesThree types of studies can be particularly useful for understanding the conformation of the CCK receptor and...

show abstract