2z60

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|SITE=
|SITE=
|LIGAND= <scene name='pdbligand=P3Y:5-[3-(2-METHOXYPHENYL)-1H-PYRROLO[2,3-B]PYRIDIN-5-YL]-N,N-DIMETHYLPYRIDINE-3-CARBOXAMIDE'>P3Y</scene>
|LIGAND= <scene name='pdbligand=P3Y:5-[3-(2-METHOXYPHENYL)-1H-PYRROLO[2,3-B]PYRIDIN-5-YL]-N,N-DIMETHYLPYRIDINE-3-CARBOXAMIDE'>P3Y</scene>
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|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]
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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>
|GENE=
|GENE=
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|DOMAIN=
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|RELATEDENTRY=[[2qoh|2QOH]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2z60 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2z60 OCA], [http://www.ebi.ac.uk/pdbsum/2z60 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2z60 RCSB]</span>
}}
}}
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[[Category: Zhou, T.]]
[[Category: Zhou, T.]]
[[Category: Zhu, X.]]
[[Category: Zhu, X.]]
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[[Category: P3Y]]
 
[[Category: abl]]
[[Category: abl]]
[[Category: alternative splicing]]
[[Category: alternative splicing]]
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[[Category: transferase]]
[[Category: transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:52:22 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:18:54 2008''

Revision as of 02:18, 31 March 2008

Image:2z60.gif


PDB ID 2z60

Drag the structure with the mouse to rotate
, resolution 1.95Å
Ligands:
Activity: Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Related: 2QOH


Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



Crystal Structure of the T315I Mutant of Abl kinase bound with PPY-A


Overview

Imatinib (Gleevec) is currently the frontline therapy for chronic myeloid leukemia (CML), a disease characterized by the presence of a constitutively activated chimeric tyrosine kinase protein Bcr-AbI. However, drug resistance often occurs at later stages of the disease, principally because of the occurrence of mutations in the kinase domain. Second generation Bcr-AbI inhibitors, such as dasatinib and nilotinib are capable of inhibiting many imatinib-resistant forms of the kinase but not the form in which threonine is mutated to isoleucine at the gatekeeper position (T315I). In this study, we present the crystal structure of the kinase domain of the c-AbI T315I mutant, as well as the wild-type form, in complex with a pyrrolopyridine inhibitor, PPY-A. The side chain of Ile315 is accommodated in the AbI T315I mutant structure without large conformational changes proximal to the site of mutation. In contrast to other inhibitors, such as imatinib and dasatinib, PPY-A does not occupy the hydrophobic pocket behind the gatekeeper residue. This binding mode, coupled with augmented contacts with the glycine-rich loop, appears to be critical for its ability to override the T315I mutation. The data presented here may provide structural guidance for the design of clinically useful inhibitors of Bcr-AbI T315I.

About this Structure

2Z60 is a Single protein structure of sequence from Mus musculus. Full crystallographic information is available from OCA.

Reference

Crystal structure of the T315I mutant of AbI kinase., Zhou T, Parillon L, Li F, Wang Y, Keats J, Lamore S, Xu Q, Shakespeare W, Dalgarno D, Zhu X, Chem Biol Drug Des. 2007 Sep;70(3):171-81. PMID:17718712

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