Modeled structure of a G-protein-coupled receptor: the cholecystokinin-1 receptor.
The Cholecystokinin-1 receptor (CCK1R) mediates actions of CCK in areas of the central nervous system and of the gut. It is a potential target to treat a number of diseases. As for all G-protein-coupled receptors, docking of ligands into modeled CCK1R binding site should greatly help to understand intrinsic mechanisms of activation. Here, we describe the procedure we used to progressively build a structural model for the CCK1R, to integrated, and on the basis of site-directed mutagenesis data on its binding site. Reliability of the CCK1R model was confirmed by interaction networks that involved conserved and functionally crucial motifs in G-protein-coupled receptors, such as Glu/Asp-Arg-Tyr and Asn-Pro-Xaa-Xaa-Tyr motifs. In addition, the 3-D structure of CCK1R-bound CCK resembled that determined by NMR in a lipid environment. The derived computational model was also used for revealing binding modes of several nonpeptide ligands and for rationalizing ligand structure-activity relationships known from experiments. Our findings indeed support that our "validated CCK1R model" could be used to study the intrinsic mechanism of CCK1R activation and design new ligands.
Archer-Lahlou
Elodie
E
INSERM U 531, Institut Louis Bugnard, CHU Rangueil, Bat. L3, 31403 Toulouse Cedex 4, France.
Tikhonova
Irina
I
Escrieut
Chantal
C
Dufresne
Marlène
M
Seva
Catherine
C
Pradayrol
Lucien
L
Moroder
Luis
L
Maigret
Bernard
B
Fourmy
Daniel
D
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001570:Benzodiazepinones / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D002766:Cholecystokinin / Q000737:chemistry / Q000378:metabolism; D020109:Devazepide / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007210:Indoleacetic Acids / Q000737:chemistry / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010671:Phenylurea Compounds / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D043886:Receptor, Cholecystokinin A / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012243:Rhodopsin / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism
D001570:Benzodiazepinones; D007210:Indoleacetic Acids; D007211:Indoles; D008024:Ligands; D008055:Lipids; D010671:Phenylurea Compounds; D043886:Receptor, Cholecystokinin A; C118846:SR 146131; D013844:Thiazoles; C080460:SR 27897; C058121:L 365260; D012243:Rhodopsin; D002766:Cholecystokinin; D020109:Devazepide