2f4j

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|PDB= 2f4j |SIZE=350|CAPTION= <scene name='initialview01'>2f4j</scene>, resolution 1.91&Aring;
|PDB= 2f4j |SIZE=350|CAPTION= <scene name='initialview01'>2f4j</scene>, resolution 1.91&Aring;
|SITE=
|SITE=
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|LIGAND= <scene name='pdbligand=VX6:CYCLOPROPANECARBOXYLIC ACID {4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE'>VX6</scene>
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|LIGAND= <scene name='pdbligand=VX6:CYCLOPROPANECARBOXYLIC+ACID+{4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE'>VX6</scene>
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|ACTIVITY= [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2]
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|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span>
|GENE= ABL1, ABL, JTK7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
|GENE= ABL1, ABL, JTK7 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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|DOMAIN=
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2f4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2f4j OCA], [http://www.ebi.ac.uk/pdbsum/2f4j PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2f4j RCSB]</span>
}}
}}
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[[Category: Young, M A.]]
[[Category: Young, M A.]]
[[Category: Zarrinkar, P.]]
[[Category: Zarrinkar, P.]]
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[[Category: VX6]]
 
[[Category: abl]]
[[Category: abl]]
[[Category: kinase]]
[[Category: kinase]]
[[Category: kinase inhibitor]]
[[Category: kinase inhibitor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 16:47:59 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:57:51 2008''

Revision as of 23:57, 30 March 2008

Image:2f4j.gif


PDB ID 2f4j

Drag the structure with the mouse to rotate
, resolution 1.91Å
Ligands:
Gene: ABL1, ABL, JTK7 (Homo sapiens)
Activity: Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2
Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



Structure of the Kinase Domain of an Imatinib-Resistant Abl Mutant in Complex with the Aurora Kinase Inhibitor VX-680


Overview

We present a high-resolution (2.0 A) crystal structure of the catalytic domain of a mutant form of the Abl tyrosine kinase (H396P; Abl-1a numbering) that is resistant to the Abl inhibitor imatinib. The structure is determined in complex with the small-molecule inhibitor VX-680 (Vertex Pharmaceuticals, Cambridge, MA), which blocks the activity of various imatinib-resistant mutant forms of Abl, including one (T315I) that is resistant to both imatinib and BMS-354825 (dasatinib), a dual Src/Abl inhibitor that seems to be clinically effective against all other imatinib-resistant forms of BCR-Abl. VX-680 is shown to have significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples. The Abl kinase domain bound to VX-680 is not phosphorylated on the activation loop in the crystal structure but is nevertheless in an active conformation, previously unobserved for Abl and inconsistent with the binding of imatinib. The adoption of an active conformation is most likely the result of synergy between the His(396)Pro mutation, which destabilizes the inactive conformation required for imatinib binding, and the binding of VX-680, which favors the active conformation through hydrogen bonding and steric effects. VX-680 is bound to Abl in a mode that accommodates the substitution of isoleucine for threonine at residue 315 (the "gatekeeper" position). The avoidance of the innermost cavity of the Abl kinase domain by VX-680 and the specific recognition of the active conformation explain the effectiveness of this compound against mutant forms of BCR-Abl, including those with mutations at the gatekeeper position.

About this Structure

2F4J is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structure of the kinase domain of an imatinib-resistant Abl mutant in complex with the Aurora kinase inhibitor VX-680., Young MA, Shah NP, Chao LH, Seeliger M, Milanov ZV, Biggs WH 3rd, Treiber DK, Patel HK, Zarrinkar PP, Lockhart DJ, Sawyers CL, Kuriyan J, Cancer Res. 2006 Jan 15;66(2):1007-14. PMID:16424036

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