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Crystallographic comparison of nicotinic ligands in complex with the acetylcholine binding protein
Author(s) -
Talley Todd T.,
Park John F.,
Wu Joshua,
Ho KwokYiu,
Sankaran Banumathi,
Taylor Palmer
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.579.4
Subject(s) - chemistry , protonation , ligand (biochemistry) , hydrogen bond , nicotinic acetylcholine receptor , protein subunit , stereochemistry , nicotinic agonist , combinatorial chemistry , molecule , biochemistry , receptor , organic chemistry , ion , gene
Since the first report of the acetylcholine binding proteins in 2001 a number of X‐ray structures of these proteins in complex with various ligands have been published. Close to 30 structures are publicly available and many still in preparation. The structures consist of peptide toxins, small alkaloid natural products, macrocyclic amines isolated from marine organisms, synthetic and semi‐synthetic pesticides including the neonicotinoids as well as compounds with therapeutic potential. Analyses of these structures highlight many molecular features that contribute to ligand recognition and selectivity. One reoccurring determinant is that tertiary and secondary nitrogen containing ligands show a precise distance relationship with a hydrogen bond from a protonated amine donor to the carbonyl oxygen of Trp 143. In contrast, quaternary ligands are stabilized by an aromatic nest with cation‐π quadrupole interactions being dominant. Many ligands also rely on topographical features removed from this central core forming bonding interactions along the subunit interface and with specific residues present in the complementary subunit. These multiple points of contact allow ligands to select and stabilize specific conformational states of the binding proteins providing a template for the design of new ligands with the potential for greater specificity and efficacy. Supported by R37 GM 108360 and U01 DA 019372.