1t46

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[[Image:1t46.gif|left|200px]]
[[Image:1t46.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 1t46 |SIZE=350|CAPTION= <scene name='initialview01'>1t46</scene>, resolution 1.60&Aring;
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The line below this paragraph, containing "STRUCTURE_1t46", creates the "Structure Box" on the page.
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|SITE=
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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=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=STI:4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE'>STI</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/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>
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or leave the SCENE parameter empty for the default display.
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|GENE= kit ([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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{{STRUCTURE_1t46| PDB=1t46 | SCENE= }}
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|RELATEDENTRY=[[1pkg|1PKG]], [[1t45|1T45]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1t46 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1t46 OCA], [http://www.ebi.ac.uk/pdbsum/1t46 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1t46 RCSB]</span>
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}}
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'''STRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF C-KIT TYROSINE KINASE'''
'''STRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF C-KIT TYROSINE KINASE'''
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[[Category: Wilson, K P.]]
[[Category: Wilson, K P.]]
[[Category: Zou, H.]]
[[Category: Zou, H.]]
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[[Category: gleevec]]
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[[Category: Gleevec]]
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[[Category: inhibitor]]
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[[Category: Inhibitor]]
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[[Category: kinase]]
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[[Category: Kinase]]
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[[Category: sti-571]]
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[[Category: Sti-571]]
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[[Category: structure]]
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[[Category: Structure]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 09:30:12 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:51:00 2008''
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Revision as of 06:30, 3 May 2008

Image:1t46.gif

Template:STRUCTURE 1t46

STRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF C-KIT TYROSINE KINASE


Overview

The activity of the c-Kit receptor protein-tyrosine kinase is tightly regulated in normal cells, whereas deregulated c-Kit kinase activity is implicated in the pathogenesis of human cancers. The c-Kit juxtamembrane region is known to have an autoinhibitory function; however the precise mechanism by which c-Kit is maintained in an autoinhibited state is not known. We report the 1.9-A resolution crystal structure of native c-Kit kinase in an autoinhibited conformation and compare it with active c-Kit kinase. Autoinhibited c-Kit is stabilized by the juxtamembrane domain, which inserts into the kinase-active site and disrupts formation of the activated structure. A 1.6-A crystal structure of c-Kit in complex with STI-571 (Imatinib or Gleevec) demonstrates that inhibitor binding disrupts this natural mechanism for maintaining c-Kit in an autoinhibited state. Together, these results provide a structural basis for understanding c-Kit kinase autoinhibition and will facilitate the structure-guided design of specific inhibitors that target the activated and autoinhibited conformations of c-Kit kinase.

About this Structure

1T46 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase., Mol CD, Dougan DR, Schneider TR, Skene RJ, Kraus ML, Scheibe DN, Snell GP, Zou H, Sang BC, Wilson KP, J Biol Chem. 2004 Jul 23;279(30):31655-63. Epub 2004 Apr 29. PMID:15123710 Page seeded by OCA on Sat May 3 09:30:12 2008

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