Methods of screening for factors that disrupt neurotrophin conformation and reduce neurotrophin biological activity

摘要

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 Zn^2+ alters the conformation of NGF rendering it unable to bind to p75^NTR or TrkA receptors or to activate signal transduction and biological outcomes normally induced by this protein. Molecular modelling studies predict that Zn^2+ binding to NGF will induce structural changes within domains of this neurotrophin which participate in the recognition of TrkA and p75^NTR. Ni^2+ on the other hand selectively alters the conformation of NGF rendering it unable to bind to TrkA but does not affect binding to p75^NTR. Similar actions of Zn^2+ are also observed with other members of the NGF family, suggesting a modulatory role for the metal ions in neurotrophin function.