Crystal Structures of the Kinase Domain of c-Abl in Complex with the Small Molecule Inhibitors PD173955 and STI571


Bhushan Nagar, William Bornmann, Patricia Pellicena, Thomas Schindler, Darren Veach, W. Todd Miller, Bayard Clarkson, and John Kuriyan


Cancer Research 62, 4236-4243, August 1, 2002

Abstract / Figures from the paper / PDB coordinates / PyMol Demo /


Abstract: The inadvertent fusion of the bcr gene with the abl gene results in a constitutively active tyrosine kinase (Bcr-Abl) that transforms cells and causes chronic myelogenous leukemia (CML). Small molecule inhibitors of Bcr-Abl that bind to the kinase domain can be used to treat CML. We report crystal structures of the kinase domain of Abl in complex with two such inhibitors, STI571 (GleevecTM, Novartis) and PD173955 (Parke-Davis). Both compounds bind to the canonical ATP-binding site of the kinase domain but do so in different ways. As shown previously in a crystal structure of Abl bound to a smaller variant of STI571, STI571 captures a specific inactive conformation of the activation loop of Abl in which the loop mimics bound peptide substrate. In contrast, PD173955 binds to a conformation of Abl in which the activation loop resembles that of an active kinase. The structure suggests that PD173955 would be insensitive to whether the conformation of the activation loop corresponds to active kinases or to that seen in the STI571 complex. In vitro kinase assays confirm this is the case and indicate that PD173955 is at least 10-fold more inhibitory than STI571. The structures suggest that PD173955 achieves its greater potency over STI571 by being able to target multiple forms of Abl (active or inactive), whereas STI571 requires a specific inactive conformation of Abl.


Illustrations from the paper. Click on the small image to get a bigger one.








The following image is from "Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia" Neil P. Shah, John M. Nicoll, Bhushan Nagar, Mercedes E. Gorre, Ronald L. Paquette, John Kuriyan, and Charles L. Sawyers


PDB Coordinates

Protein Structure Coordinates and X-ray Structure Factors of Abl:STI571 complex (PDB code 1IEP)

Protein Structure Coordinates and X-ray Structure Factors of Abl:PD173955 complex (PDB code 1M52)