1M52

Crystal Structure of the c-Abl Kinase domain in complex with PD173955

Summary for 1M52

• Entry DOI: 10.2210/pdb1m52/pdb
• Related: 1IEP
• Descriptor: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ABL1, 6-(2,6-DICHLORO-PHENYL)-8-METHYL-2-(3-METHYLSULFANYL-PHENYLAMINO)-8H-PYRIDO[2,3-D]PYRIMIDIN-7-ONE, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: kinase, kinase inhibitor, pd173955, activation loop, transferase
• Biological source: Mus musculus (house mouse)
• Cellular location: Cytoplasm, cytoskeleton: P00520
• Total number of polymer chains: 2
• Total formula weight: 68764.22

Authors

Nagar, B.,Bornmann, W.,Pellicena, P.,Schindler, T.,Veach, D.,Miller, W.T.,Clarkson, B.,Kuriyan, J. (deposition date: 2002-07-08, release date: 2002-09-18, Last modification date: 2024-02-14)

Primary citation

Nagar, B.,Bornmann, W.,Pellicena, P.,Schindler, T.,Veach, D.,Miller, W.T.,Clarkson, B.,Kuriyan, J.
Crystal Structures of the Kinase Domain of c-Abl in Complex with the Small Molecule Inhibitors PD173955 and Imatinib (STI-571)
Cancer Res., 62:4236-4243, 2002

PubMed 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. Small molecule inhibitors of Bcr-Abl that bind to the kinase domain can be used to treat chronic myelogenous leukemia. We report crystal structures of the kinase domain of Abl in complex with two such inhibitors, imatinib (also known as STI-571 and Gleevec) and PD173955 (Parke-Davis). Both compounds bind to the canonical ATP-binding site of the kinase domain, but they do so in different ways. As shown previously in a crystal structure of Abl bound to a smaller variant of STI-571, STI-571 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 STI-571 complex. In vitro kinase assays confirm that this is the case and indicate that PD173955 is at least 10-fold more inhibitory than STI-571. The structures suggest that PD173955 achieves its greater potency over STI-571 by being able to target multiple forms of Abl (active or inactive), whereas STI-571 requires a specific inactive conformation of Abl.

PubMed: 12154025

Experimental method

X-RAY DIFFRACTION (2.6 Å)