METHODS FOR FOR MODELING GPCRS AND FOR PRODUCING LIGAND BLOCKING AND RECEPTOR ACTIVATING ANTIBODIES FOR SAME

A method for modeling G protein coupled receptors (GPCR) and producing conformationally constrained peptides or fragments thereof that generally includes the steps of: providing a molecular model of a GPCR and identifying a peptide sequence therein, having at least one peptide residue involved in ligand binding; identifying a plurality of amino acid sequences extracellular and proximal to at least one transmembrane domain and at least one extracellular loop; identifying at least one amino acid on said loop as an optimal location for a conformational constraint in said extracellular loop; mutating said identified amino acid to cysteine if not already cysteine; covalently connecting one or more linkers to said cysteine to conformationally constrain said peptide; and characterizing said constrained peptide using nuclear magnetic resonance (NMR) to verify a stable tertiary structure having conformations substantially similar to overlapping regions of a molecular model of said modeled GPCR containing said peptide.