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 kno wn as ephrins, represent the largest subfamily of receptor tyrosine kinases (RTKs)(1). They are predominantly expressed in the developing and adult ne rvous system(2) and are important in contact-mediated axon guidance(3-6), a xon fasciculation(5,7) and cell migations(8-11). Eph receptors are unique a mong other RTKs in that they fall into two subclasses with distinct Ligand specificities(12), and in that they can themselves function as ligands to a ctivate bidirectional cell-cell signalling(4,13,14). We report here the cry stal structure at 2.9 Angstrom resolution of the amino-terminal ligand-bind ing domain of the EphB2 receptor (also known as NUk)(15-17). Th, domain fol ds into a compact jellyroll beta-sandwich composed of 11 antiparallel beta- 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 agains t the concave beta-sandwich surface near positions at which missense mutati ons cause signalling defects(18), localizing the ligand-binding region on t he surface of the receptor.