Factors and methods for disrupting or inhibiting the association of protomers of a multimeric protein are described. Such inhibition reduces the biological disorders. Particularly, novel neurotrophin antagonists are described. Generally, the antagonist comprises amino acids from positions 68-58 and 108-110 of a neurotrophin, in which the amino acid from position 68 is covalently bound to the amino acid from position 108 and the amino acid from position 58 is covalently bound to the amino acid at position 110 to form a bicyclic structure, in another aspect of the invention transition metal ions are provided for selectively altering the geometry of the receptor binding domains of neurotrophins which allows functionality and activity of the neurotrophins to be selectively reduced. For example Zn2+ alters the conformation of NGF rendering it unable to bind to p75NTR or TrkA receptors or to activate signal transduction and biological outcomes normally induced by this protein. Molecular modelling studies predict that Zn2+ binding to NGF will induce structural changes within domains of this neurotrophin which participate in the recognition of TrkA and p75NTR. Ni2+ on the other hand selectively alters the conformation of NGF rendering it unable to bind to TrkA but does not affect binding to p75NTR. Similar actions of Zn2+ are also observed with other members of the NGF family, suggesting a modulatory role for the metal ions in neurotrophin function.
Methods of screening for factors that disrupt neurotrophin conformation and reduce neurotrophin biological activity