Abl Tyrosine Kinase

Our studies on the Src kinases lead directly to our interest in the Abelson leukemia virus tyrosine kinase (v-Abl) and its cellular counterpart, c-Abl.

c-Abl is a much larger protein than c-Src, but its N-terminal half is very closely related to the Src kinases:

What's interesting about c-Abl is that the tyrosine residue (Tyr 527) that is crucial for the regulation of the Src kinases is missing in c-Abl, and yet the SH2 and SH3 domains are somehow involved in keeping the activity of the tyrosine kinase under control.

We are also using a combination of techniques to understand how a drug known as Gleevec (Imitanib, STI-571, Novartis) achieves specificity for its target. Gleevec is used to treat chronic myelogeneous leukemia (CML), a deadly disease if untreated, and it acts by blocking the kinase activity of a protein known as BCR-Abl, which is improperly activated in the disease. BCR-Abl is a fusion between the BCR protein and the Abl tyrosine kinase, which results in the improper activation of the catalytic activity of Abl.

We have determined the crystal structure of the kinase domain of Abl in complex with Gleevec and have shown that the inhibitor recognizes an inactive conformation of Abl.

This is movie showing the complex of Gleevec and the kinase domain of Abl. Click on it to start the movie.

The fact that Gleevec recognizes a distorted conformation of the Abl kinase domain provides clues as to why Gleevec inhibits Abl (and BCR-Abl), but not Src. At first glance this is quite puzzling, since essentially every residue that touches the drug in our crystal structure of Abl is conserved in the Src kinases. It turns out that the inactive conformation of Abl recognized by Gleevec is quite distinct structurally from the inactive conformations seen previously for the Src kinases, and indeed Gleevec cannot fit into the inactive Src and Hck structures. Upon further consideration things do not remain so simple. The kinase domains of Src and Abl are so closely related in sequence that it is not obvious why the Src kinases cannot distort into a conformation that could accommodate Geevec. We are investigating these questions, as well as the role of the regulatory domains of Abl in controlling the activity of the kinase.

This analysis of the Abl-Gleevec structure highlights the important role that the conformational plasticity of protein kinases can play in providing routes for the development of specific small molecule inhibitors of kinases. Although the hundreds of proteins kinases encoded by the human genome are structurally very similar, their conformational dynamics differ. Understanding these dynamics is an important continuing part of our research.