Crystal structure of the EphA4 protein tyrosine kinase domain in the apo- and dasatinib-bound state

Carine Farenc; Patrick H N Celie; Cornelis P Tensen; Iwan J P de Esch; Gregg Siegal

doi:10.1016/j.febslet.2011.10.028

Crystal structure of the EphA4 protein tyrosine kinase domain in the apo- and dasatinib-bound state

FEBS Lett. 2011 Nov 16;585(22):3593-9. doi: 10.1016/j.febslet.2011.10.028. Epub 2011 Oct 22.

Authors

Carine Farenc¹, Patrick H N Celie, Cornelis P Tensen, Iwan J P de Esch, Gregg Siegal

Affiliation

¹ Protein Chemistry Group, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands.

PMID: 22036717
DOI: 10.1016/j.febslet.2011.10.028

Abstract

The Eph family of receptor tyrosine kinases regulates diverse cellular processes while the over-expression of a member of this family, EphA4, has been reported in a variety of malignant carcinomas. To gain insight into molecular mechanisms and to facilitate structure-based inhibitor design, we solved the crystal structure of the native EphA4 kinase domain in both the apo and dasatinib bound forms. Analysis of the two structures provides insight into structural features of inhibitor binding and revealed a hydrophobic back-pocket in the ATP- binding site of EphA4 which was previously unidentified. The structures suggest a route towards development of novel and specific inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / chemistry
Amino Acid Sequence
Animals
Antineoplastic Agents / chemistry*
Binding Sites
Catalytic Domain
Crystallography, X-Ray
Dasatinib
Hydrophobic and Hydrophilic Interactions
Ligands
Mice
Models, Molecular
Molecular Sequence Data
Pyrimidines / chemistry*
Receptor, EphA4 / antagonists & inhibitors
Receptor, EphA4 / chemistry*
Thiazoles / chemistry*

Substances

Antineoplastic Agents
Ligands
Pyrimidines
Thiazoles
Adenosine Triphosphate
Receptor, EphA4
Dasatinib

Associated data

PDB/2Y6M
PDB/2Y6O