Crystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2

The Eph receptors, which bind a group of cell-membrane-anchored ligands known as ephrins, represent the largest subfamily of receptor tyrosine kinases (RTKs)1. They are predominantly expressed in the developing and adult nervous system2 and are important in contact-mediated axon guidance3,4,5,6, axon fasciculation5,7 and cell migration8,9,10,11. Eph receptors are unique among other RTKs in that they fall into two subclasses with distinct ligand specificities12, and in that they can themselves function as ligands to activate bidirectional cell–cell signalling4,13,14. We report here the crystal structure at 2.9 Å resolution of the amino-terminal ligand-binding domain of the EphB2 receptor (also known as Nuk)15,16,17. The domain folds into a compact jellyroll β-sandwich composed of 11 antiparallel β-strands. Using structure-based mutagenesis, we have identified an extended loop that is important for ligand binding and class specificity. This loop, which is conserved within but not between Eph RTK subclasses, packs against the concave β-sandwich surface near positions at which missense mutations cause signalling defects18, localizing the ligand-binding region on the surface of the receptor.