title: Chemical scale studies of the Phe-Pro conserved motif in the cys loop of Cys loop receptors.
abstract: The functions of two conserved residues, Phe(135) and Pro(136), located at the apex of the Cys loop of the nicotinic acetylcholine receptor are investigated. Both residues were substituted with natural and unnatural amino acids, focusing on the role of aromaticity at Phe(135), backbone conformation at Pro(136), side chain polarity and volume, and the specific interaction between the aromatic side chain and the proline. NMR spectroscopy studies of model peptides containing proline and unnatural proline analogues following a Phe show a consistent increase in the population of the cis conformer relative to peptides lacking the Phe. In the receptor, a strong interaction between the Phe and Pro residues is evident, as is a strong preference for aromaticity and hydrophobicity at the Phe site. A similar influence of hydrophobicity is observed at the proline site. In addition, across a simple homologous series of proline analogues, the results reveal a correlation between receptor function and cis bias at the proline backbone. This could suggest a significant role for the cis proline conformer at this site in receptor function.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Walrati
authors.initials: W
authors.lastname: Limapichat
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Dougherty
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003545:Cysteine / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry*; D011392:Proline / Q000737:chemistry*; D011485:Protein Binding; D011978:Receptors, Nicotinic / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis
chemical_list: D011978:Receptors, Nicotinic; D010649:Phenylalanine; D011392:Proline; D003545:Cysteine