Orthogonal ligand-protein pair

Orthogonal ligand-protein pairs (also known as re-engineered ligand-receptor interfaces or re-engineered enzyme-substrate interactions) are a protein-ligand binding pair made to be independent of the original binding pair. This is done by taking a mutant protein (naturally occurring or selectively engineered), which is activated by a different ligand (carefully synthesized or selected). The intention here is that the orthogonal ligand will not interact with the original protein. The original protein will also be designed to not interact with the orthogonal ligand in certain cases. An example of orthogonal ligand-receptor interfaces are RASSL and DREADD. They are G protein-coupled receptors that are activated by synthesized ligands that wouldn't normally exist in the cell, such as the anti-psychotic Clozapine, allowing researchers to control the interaction externally and independent of internal activation.