2V7A

Crystal structure of the T315I Abl mutant in complex with the inhibitor PHA-739358

Summary for 2V7A

• Entry DOI: 10.2210/pdb2v7a/pdb
• Related: 1AB2 1ABL 1AWO 1BBZ 1JU5 1OPL 1ZZP 2ABL 2F4J 2FO0 2G2F 2G2H 2GQG
• Descriptor: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE ABL1, N-[(3E)-5-[(2R)-2-METHOXY-2-PHENYLACETYL]PYRROLO[3,4-C]PYRAZOL-3(5H)-YLIDENE]-4-(4-METHYLPIPERAZIN-1-YL)BENZAMIDE, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: kinase, nucleus, myristate, cytoplasm, manganese, cell adhesion, metal-binding, proto-oncogene, tyrosine-protein kinase, chromosomal rearrangement, transferase, lipoprotein, polymorphism, cytoskeleton, magnesium, sh2 domain, sh3 domain, atp-binding, nucleotide-binding, alternative splicing, phosphorylation, kinase inhibitor, t315i abl mutant
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 2
• Total formula weight: 67283.31

Authors

Modugno, M.,Casale, E.,Soncini, C.,Rosettani, P.,Colombo, R.,Lupi, R.,Rusconi, L.,Fancelli, D.,Carpinelli, P.,Cameron, A.D.,Isacchi, A.,Moll, J. (deposition date: 2007-07-27, release date: 2007-09-18, Last modification date: 2023-12-13)

Primary citation

Modugno, M.,Casale, E.,Soncini, C.,Rosettani, P.,Colombo, R.,Lupi, R.,Rusconi, L.,Fancelli, D.,Carpinelli, P.,Cameron, A.D.,Isacchi, A.,Moll, J.
Crystal Structure of the T315I Abl Mutant in Complex with the Aurora Kinases Inhibitor Pha-739358.
Cancer Res., 67:7987-, 2007

PubMed Abstract: Mutations in the kinase domain of Bcr-Abl are the most common cause of resistance to therapy with imatinib in patients with chronic myelogenous leukemia (CML). Second-generation Bcr-Abl inhibitors are able to overcome most imatinib-resistant mutants, with the exception of the frequent T315I substitution, which is emerging as a major cause of resistance to these drugs in CML patients. Structural studies could be used to support the drug design process for the development of inhibitors able to target the T315I substitution, but until now no crystal structure of the T315I Abl mutant has been solved. We show here the first crystal structure of the kinase domain of Abl T315I in complex with PHA-739358, an Aurora kinase inhibitor currently in clinical development for solid and hematologic malignancies. This compound inhibits in vitro the kinase activity of wild-type Abl and of several mutants, including T315I. The cocrystal structure of T315I Abl kinase domain provides the structural basis for this activity: the inhibitor associates with an active conformation of the kinase domain in the ATP-binding pocket and lacks the steric hindrance imposed by the substitution of threonine by isoleucine.

PubMed: 17804707
DOI: 10.1158/0008-5472.CAN-07-1825

Experimental method

X-RAY DIFFRACTION (2.5 Å)