Eph receptors are the largest family of receptor tyrosine kinases. Eph-RTKs and their ligands, ephrins, are predominantly expressed in the developing and adult nervous system and have a key role in axon guidance, fasciculation, and cell migration. The applicant proposes to characterize Eph-receptor/ephrin interactions, through crystallographic studies. The crystal structure of the ligand-binding domain of Eph-B2 (a class B receptor) has been determined, revealing a jelly-roll architecture related to the sialic- acid binding domain of flu HA. Crystallographic analyses of the class A Eph receptors and of both classes of ephrins are planned. The focus will be on identification of structural elements the contribute to receptor-ligand recognition and class (A/B) discrimination. Structures of complexes will also be analyzed. These comparative crystallographic studies will define the structural basis of the high promiscuity of Eph- RTK/ephrin interactions within the classes, but lack of cross- interaction between classes. The kinetics and thermodynamics of these interactions will also be determined.
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