2v7a

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[[Image:2v7a.jpg|left|200px]]
[[Image:2v7a.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 2v7a |SIZE=350|CAPTION= <scene name='initialview01'>2v7a</scene>, resolution 2.50&Aring;
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The line below this paragraph, containing "STRUCTURE_2v7a", creates the "Structure Box" on the page.
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|SITE= <scene name='pdbsite=AC1:Mg+Binding+Site+For+Chain+B'>AC1</scene>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|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>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|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>
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|GENE=
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|DOMAIN=
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{{STRUCTURE_2v7a| PDB=2v7a | SCENE= }}
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|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]]
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|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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}}
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'''CRYSTAL STRUCTURE OF THE T315I ABL MUTANT IN COMPLEX WITH THE INHIBITOR PHA-739358'''
'''CRYSTAL STRUCTURE OF THE T315I ABL MUTANT IN COMPLEX WITH THE INHIBITOR PHA-739358'''
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[[Category: Rusconi, L.]]
[[Category: Rusconi, L.]]
[[Category: Soncini, C.]]
[[Category: Soncini, C.]]
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[[Category: alternative splicing]]
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[[Category: Alternative splicing]]
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[[Category: atp-binding]]
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[[Category: Atp-binding]]
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[[Category: cell adhesion]]
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[[Category: Cell adhesion]]
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[[Category: chromosomal rearrangement]]
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[[Category: Chromosomal rearrangement]]
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[[Category: cytoplasm]]
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[[Category: Cytoplasm]]
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[[Category: cytoskeleton]]
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[[Category: Cytoskeleton]]
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[[Category: kinase]]
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[[Category: Kinase]]
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[[Category: kinase inhibitor]]
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[[Category: Kinase inhibitor]]
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[[Category: lipoprotein]]
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[[Category: Lipoprotein]]
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[[Category: magnesium]]
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[[Category: Magnesium]]
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[[Category: Manganese]]
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[[Category: metal-binding]]
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[[Category: Metal-binding]]
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[[Category: myristate]]
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[[Category: Myristate]]
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[[Category: nucleotide-binding]]
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[[Category: Nucleotide-binding]]
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[[Category: Nucleus]]
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[[Category: phosphorylation]]
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[[Category: Phosphorylation]]
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[[Category: polymorphism]]
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[[Category: Polymorphism]]
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[[Category: proto-oncogene]]
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[[Category: Proto-oncogene]]
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[[Category: sh2 domain]]
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[[Category: Sh2 domain]]
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[[Category: sh3 domain]]
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[[Category: Sh3 domain]]
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[[Category: t315i abl mutant]]
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[[Category: T315i abl mutant]]
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[[Category: transferase]]
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[[Category: Transferase]]
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[[Category: tyrosine-protein kinase]]
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[[Category: Tyrosine-protein kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 18:18:59 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:09:08 2008''
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Revision as of 15:19, 4 May 2008

Image:2v7a.jpg

Template:STRUCTURE 2v7a

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 Sun May 4 18:18:59 2008

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