Modeling of agonist binding to the ligand-gated ion channel superfamily of receptors.
A generalized model is presented of agonist binding to ligand-gated ion channels (LGICs). Broad similarity in the structure of agonists suggests that the binding sites of LGICs may have evolved from a protobinding site. Aligned sequence data identified as a candidate for such a site a highly conserved 15 residue stretch of primary structure in the N-terminal extracellular region of all known LGIC subunits. We modeled this subregion, termed the cys-loop, as a rigid, amphiphilic beta-hairpin and propose that it may form a major determinant of a conserved structural binding cleft. In the model of the binding complex (1) an invariant aspartate residue at position 11 of the cys-loop is the anionic site interacting with the positively charged amine group of agonists, (2) a local dipole within the pi-electron system of agonists is favorably oriented in the electrostatic field of the invariant aspartate, (3) the epsilon ring-proton of a conserved aromatic residue at the turn of the cys-loop interacts orthogonally with the agonist pi-electron density at its electronegative center, and (4) selective recognition is partly a result of the type of amino acid residue at position 6 of the cys-loop. Additionally, formation of a hydrogen bond between the electronegative atom of the pi-electron system of agonist and a complementary group in the receptor may be important in the high-affinity binding of agonists.
Cockcroft
V B
VB
Molecular Graphics Unit, Bath University, UK.
Osguthorpe
D J
DJ
Barnard
E A
EA
Lunt
G G
GG
D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011963:Receptors, GABA-A / Q000378:metabolism* / Q000648:ultrastructure; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter / Q000378:metabolism* / Q000648:ultrastructure; D011978:Receptors, Nicotinic / Q000378:metabolism* / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D008024:Ligands; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; D011978:Receptors, Nicotinic