Cation-pi interactions in ligand recognition by serotonergic (5-HT3A) and nicotinic acetylcholine receptors: the anomalous binding properties of nicotine.
A series of tryptophan analogues has been introduced into the binding site regions of two ion channels, the ligand-gated nicotinic acetylcholine and serotonin 5-HT(3A) receptors, using unnatural amino acid mutagenesis and heterologous expression in Xenopus oocytes. A cation-pi interaction between serotonin and Trp183 of the serotonin channel 5-HT(3A)R is identified for the first time, precisely locating the ligand-binding site of this receptor. The energetic contribution of the observed cation-pi interaction between a tryptophan and the primary ammonium ion of serotonin is estimated to be approximately 4 kcal/mol, while the comparable interaction with the quaternary ammonium of acetylcholine is approximately 2 kcal/mol. The binding mode of nicotine to the nicotinic receptor of mouse muscle is examined by the same technique and found to differ significantly from that of the natural agonist, acetylcholine.
Beene
Darren L
DL
Divisions of Chemistry and Chemical Engineering and Biology, California Institute of Technology, Pasadena, California 91125, USA.
Brandt
Gabriel S
GS
Zhong
Wenge
W
Zacharias
Niki M
NM
Lester
Henry A
HA
Dougherty
Dennis A
DA
D000478:Alkylation; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002412:Cations / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D005462:Fluorine Radioisotopes; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009538:Nicotine / Q000031:analogs & derivatives* / Q000737:chemistry*; D018408:Patch-Clamp Techniques; D011726:Pyridinium Compounds / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000235:genetics; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000235:genetics; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin / Q000031:analogs & derivatives* / Q000737:chemistry; D017366:Serotonin Receptor Agonists / Q000737:chemistry; D055672:Static Electricity; D014364:Tryptophan / Q000031:analogs & derivatives / Q000737:chemistry; D014982:Xenopus laevis
D002412:Cations; D005462:Fluorine Radioisotopes; D008024:Ligands; D011726:Pyridinium Compounds; D011978:Receptors, Nicotinic; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D017366:Serotonin Receptor Agonists; C042390:alpha-methylserotonin; C047661:N-methylnicotinium; D012701:Serotonin; D009538:Nicotine; D014364:Tryptophan