1t45
From Proteopedia
(New page: 200px<br /><applet load="1t45" size="450" color="white" frame="true" align="right" spinBox="true" caption="1t45, resolution 1.90Å" /> '''STRUCTURAL BASIS FOR...) |
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| - | [[Image:1t45.jpg|left|200px]]<br /><applet load="1t45" size=" | + | [[Image:1t45.jpg|left|200px]]<br /><applet load="1t45" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1t45, resolution 1.90Å" /> | caption="1t45, resolution 1.90Å" /> | ||
'''STRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF C-KIT TYROSINE KINASE'''<br /> | '''STRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF C-KIT TYROSINE KINASE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The activity of the c-Kit receptor protein-tyrosine kinase is tightly | + | 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== | ==About this Structure== | ||
| - | 1T45 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [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] Full crystallographic information is available from [http:// | + | 1T45 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1T45 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
| - | [[Category: Dougan, D | + | [[Category: Dougan, D R.]] |
| - | [[Category: Kraus, M | + | [[Category: Kraus, M L.]] |
| - | [[Category: Mol, C | + | [[Category: Mol, C D.]] |
| - | [[Category: Sang, B | + | [[Category: Sang, B C.]] |
| - | [[Category: Scheibe, D | + | [[Category: Scheibe, D N.]] |
| - | [[Category: Schneider, T | + | [[Category: Schneider, T R.]] |
| - | [[Category: Skene, R | + | [[Category: Skene, R J.]] |
| - | [[Category: Snell, G | + | [[Category: Snell, G P.]] |
| - | [[Category: Wilson, K | + | [[Category: Wilson, K P.]] |
[[Category: Zou, H.]] | [[Category: Zou, H.]] | ||
[[Category: autoinhibition]] | [[Category: autoinhibition]] | ||
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[[Category: structure]] | [[Category: structure]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:09:42 2008'' |
Revision as of 13:09, 21 February 2008
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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
1T45 is a Single protein structure of sequence from Homo sapiens. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 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 Thu Feb 21 15:09:42 2008
Categories: Homo sapiens | Single protein | Transferase | Dougan, D R. | Kraus, M L. | Mol, C D. | Sang, B C. | Scheibe, D N. | Schneider, T R. | Skene, R J. | Snell, G P. | Wilson, K P. | Zou, H. | Autoinhibition | Kinase | Structure
