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Modeling of agonist binding to the ligand‐gated ion channel superfamily of receptors
Author(s) -
Cockcroft Victor B.,
Osguthorpe David J.,
Barnard Eric A.,
Lunt George G.
Publication year - 1990
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.340080412
Subject(s) - agonist , chemistry , stereochemistry , binding site , receptor , residue (chemistry) , ion channel , biochemistry
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 β‐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 π‐electron system of agonists is favorably oriented in the electrostatic field of the invariant aspartate, (3) the ε ring‐proton of a conserved aromatic residue at the turn of the cys ‐loop interacts orthogonally with the agonist α‐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, the formation of a hydrogen bond between the electronegative atom of the π‐electron system of agonist and a complementary group in the receptor may be important in the high‐affinity binding of agonists.