ADGRL4/ELTD1 is a highly conserved angiogenesis-associated orphan adhesion GPCR that emerged with the first vertebrates and comprises 3 evolutionary variants.

This work establishes ADGRL4/ELTD1's evolution, sheds light on its possible activation and ligand binding zones, and establishes the first temporal references for the emergence of ADGRL4/ELTD1 variants during vertebrate evolution. Our approach is applicable to the greater aGPCR family and opens up new avenues for future experimental work.