Exploring enantiospecific ligand-protein interactions using cellular membrane affinity chromatography: chiral recognition as a dynamic process.
The chiral recognition mechanisms responsible for the enantioselective binding on the alpha3beta4 nicotinic acetylcholine receptor (alpha3 beta4 nAChR) and human organic cation transporter 1 (hOCT1) have been reviewed. The results indicate that chiral recognition on the alpha3beta4 nAChR is a process involving initial tethering of dextromethorphan and levomethorphan at hydrophobic pockets within the central lumen followed by hydrogen bonding interactions favoring dextromethorphan. The second step is the defining enantioselective step. Studies with the hOCT1 indentified four binding sites within the transporter that participated in chiral recognition. Each of the enantiomers of the compounds used in the study interacted with three of these sites, while (R)-verapamil interacted with all four. Chiral recognition arose from the conformational adjustments required to produce optimum interactions. With respect to the prevailing interaction-based models, the data suggest that chiral recognition is a dynamic process and that the static point-based models should be amended to reflect this.
Jozwiak
Krzysztof
K
Laboratory of Drug-Receptor Interactions, Medical University of Lublin, 20-081 Lublin, Poland.
Moaddel
Ruin
R
Ravichandran
Sarangan
S
Plazinska
Anita
A
Kozak
Joanna
J
Patel
Sharvil
S
Yamaguchi
Rika
R
Wainer
Irving W
IW
D002462:Cell Membrane / Q000378:metabolism*; D002846:Chromatography, Affinity / Q000379:methods*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D050811:Octamer Transcription Factor-1 / Q000378:metabolism*; D011433:Propranolol / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013816:Thermodynamics; D014700:Verapamil / Q000378:metabolism
D008024:Ligands; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D011506:Proteins; D011433:Propranolol; D014700:Verapamil