Evolution of gonadotropin-releasing hormone (GnRH) structure and its receptor

It is evident now that the gonadotropin-releasing hormone (GnRH) structure was already in existence very early in the evolution of animals and was co-opted in diverse ways to regulate reproduction. During 600 million years of animal evolution, the N and C termini of GnRH have been conserved as functional domains for binding and activating cognate receptors to accomplish its functions. About 400 millions years ago, a single substitution of the chiral amino acid in position 6 of GnRH in jawless fish by the achiral glycine facilitated a type II' beta-turn conformation of GnRH to allow spatially close interaction of functional domains of GnRH with receptors, in contrast to the interaction of more extended GnRH structures with their cognate receptors in earlier-evolved species. GnRH II was preconfigured to this conformation through intramolecular interactions, which accounts for its high binding affinity and total conservation of primary structure over 400 million years of evolution. It is very surprising and fascinating that the coordinated evolutionary selection of amino acids participating in binding GnRH has resulted in such perfection, that no substitution with a natural amino acid in any position improves binding potency.