2v7a
From Proteopedia
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|PDB= 2v7a |SIZE=350|CAPTION= <scene name='initialview01'>2v7a</scene>, resolution 2.50Å | |PDB= 2v7a |SIZE=350|CAPTION= <scene name='initialview01'>2v7a</scene>, resolution 2.50Å | ||
|SITE= <scene name='pdbsite=AC1:Mg+Binding+Site+For+Chain+B'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Mg+Binding+Site+For+Chain+B'>AC1</scene> | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=627:N-[(3E)-5-[(2R)-2-METHOXY-2-PHENYLACETYL]PYRROLO[3,4-C]PYRAZOL-3(5H)-YLIDENE]-4-(4-METHYLPIPERAZIN-1-YL)BENZAMIDE'>627</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene> |
| - | |ACTIVITY= [http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] | + | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span> |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1ab2|1AB2]], [[1ju5|1JU5]], [[2f4j|2F4J]], [[2g2f|2G2F]], [[2gqg|2GQG]], [[1abl|1ABL]], [[1awo|1AWO]], [[1bbz|1BBZ]], [[1opl|1OPL]], [[1zzp|1ZZP]], [[2abl|2ABL]], [[2fo0|2FO0]], [[2g2h|2G2H]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2v7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2v7a OCA], [http://www.ebi.ac.uk/pdbsum/2v7a PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2v7a RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Leukemia, Philadelphia chromosome-positive, resistant to imatinib OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=189980 189980]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Rusconi, L.]] | [[Category: Rusconi, L.]] | ||
[[Category: Soncini, C.]] | [[Category: Soncini, C.]] | ||
| - | [[Category: 627]] | ||
| - | [[Category: MG]] | ||
[[Category: alternative splicing]] | [[Category: alternative splicing]] | ||
[[Category: atp-binding]] | [[Category: atp-binding]] | ||
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[[Category: tyrosine-protein kinase]] | [[Category: tyrosine-protein kinase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:09:08 2008'' |
Revision as of 02:09, 31 March 2008
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| , resolution 2.50Å | |||||||
|---|---|---|---|---|---|---|---|
| Sites: | |||||||
| Ligands: | , , | ||||||
| Activity: | Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 | ||||||
| Related: | 1AB2, 1JU5, 2F4J, 2G2F, 2GQG, 1ABL, 1AWO, 1BBZ, 1OPL, 1ZZP, 2ABL, 2FO0, 2G2H
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF THE T315I ABL MUTANT IN COMPLEX WITH THE INHIBITOR PHA-739358
Overview
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.
About this Structure
2V7A is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358., Modugno M, Casale E, Soncini C, Rosettani P, Colombo R, Lupi R, Rusconi L, Fancelli D, Carpinelli P, Cameron AD, Isacchi A, Moll J, Cancer Res. 2007 Sep 1;67(17):7987-90. PMID:17804707
Page seeded by OCA on Mon Mar 31 05:09:08 2008
Categories: Homo sapiens | Non-specific protein-tyrosine kinase | Single protein | Cameron, A D. | Carpinelli, P. | Casale, E. | Colombo, R. | Fancelli, D. | Isacchi, A. | Lupi, R. | Modugno, M. | Moll, J. | Rosettani, P. | Rusconi, L. | Soncini, C. | Alternative splicing | Atp-binding | Cell adhesion | Chromosomal rearrangement | Cytoplasm | Cytoskeleton | Kinase | Kinase inhibitor | Lipoprotein | Magnesium | Manganese | Metal-binding | Myristate | Nucleotide-binding | Nucleus | Phosphorylation | Polymorphism | Proto-oncogene | Sh2 domain | Sh3 domain | T315i abl mutant | Transferase | Tyrosine-protein kinase
