Anyone knows of an example of a protein that, without coming from a recent duplication event, underwent a mutation(s) that caused it to have a novel interaction with a new ligand, substrate, other protein or molecule? By novel I imply that it doesn't "go back" to an ancestral interaction or doesn’t develops an interaction that it's already performed by a close relative. I assume that these mutations are extremely rare, and that a duplicate is almost always necessary to have them fixed in a lineage.
That's easy, red blood cells and the single mutation causing the switch in charge resulting in sickle cell anaemia. There are five different convergent mutations although the concept of convergence here has been challenged. The mutation results in the physical collapse of the protein structure and massively reduces its binding with oxygen. The receptor interactions with the malarial parasite render infection of the red blood cell impossible. Even in the heterozygote state, oxygen binding with the heme group is not massively disrupted, but the ability of the malaria parasite in particular plasmodium falciparum, to invade the red blood cell is again greatly impaired. It is an incredible example of human evolution and demonstrates the selective pressure of holoedemica malaria. There is no gene duplication involved here and again due stress there are potentially 5 convergent events resulting in the same phenotype and the scale of protein collapse from circular red blood cell to sickle cell shape is the result of what would otherwise appear to be a small change in amino acid charge for a single amino acid substitution.