Identification of multiple allosteric sites on the M1 muscarinic acetylcholine receptor.
Staurosporine and four staurosporine derivatives were docked on the rhodopsin-based homology model of the M1 muscarinic acetylcholine receptor in order to localize the possible allosteric sites of this receptor. It was found that there were three major allosteric sites, two of which are located at the extracellular face of the receptor, and one in the intracellular domain of the receptor. In the present study, the localization of these binding sites is described for the first time. The present study confirms the existence of multiple allosteric sites on the M1 muscarinic receptor, and lays the ground for further experimental and computational analysis to better understand how muscarinic receptors are modulated via their allosteric sites. These findings will also help to design and develop novel drugs acting as allosteric modulators of the M1 receptor, which can be used in the treatment of the Alzheimer's disease.
Espinoza-Fonseca
L Michel
LM
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA. mef@ddt.biochem.umn.edu
Trujillo-Ferrara
José G
JG
D000465:Algorithms; D000495:Allosteric Site; D001665:Binding Sites; D002227:Carbazoles / Q000737:chemistry; D002712:Chlorides / Q000737:chemistry; D003198:Computer Simulation; D004220:Disulfides / Q000737:chemistry; D019204:GTP-Binding Proteins / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009994:Osmolar Concentration; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D043643:Receptor, Muscarinic M1 / Q000737:chemistry* / Q000378:metabolism*; D012243:Rhodopsin / Q000737:chemistry; D012964:Sodium / Q000737:chemistry; D055672:Static Electricity; D019311:Staurosporine / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
D002227:Carbazoles; D002712:Chlorides; D004220:Disulfides; D008024:Ligands; D043643:Receptor, Muscarinic M1; D012243:Rhodopsin; D012964:Sodium; D019204:GTP-Binding Proteins; D019311:Staurosporine