Structure of the EphA3 receptor/ephrin-A5 Ligand Complex

The Kuhn laboratory at the Bridge Institute at the University of Southern California and the Sanford-Burnham Medical Research Institute (La Jolla, CA) report the first crystal structure of the ligand binding domain of human EphA3 receptor in complex with its preferred ligand, ephrin-A5. EphA3 receptor, a member of the receptor tyrosine kinase family, is a frequently mutated gene in lung cancer and is also implicated in many other cancer types. This structure reveals a distinct binding orientation of ephrin-A5 with EphA3 compared to its orientation when bound to other members of the Eph receptor family.

Link to article: PLoS ONE

The Eph receptor tyrosine kinase/ephrin ligand system regulates a wide spectrum of physiological processes, while its dysregulation has been implicated in cancer progression. The human EphA3 receptor is widely upregulated in the tumor microenvironment and is highly expressed in some types of cancer cells. Furthermore, EphA3 is among the most highly mutated genes in lung cancer and it is also frequently mutated in other cancers. We report the structure of the ligand-binding domain of the EphA3 receptor in complex with its preferred ligand, ephrin-A5. The structure of the complex reveals a pronounced tilt of the ephrin-A5 ligand compared to its orientation when bound to the EphA2 and EphB2 receptors and similar to its orientation when bound to EphA4. This tilt brings an additional area of ephrin-A5 into contact with regions of EphA3 outside the ephrin-binding pocket thereby enlarging the size of the interface, which is consistent with the high binding affinity of ephrin-A5 for EphA3. This large variation in the tilt of ephrin-A5 bound to different Eph receptors has not been previously observed for other ephrins.