1t45: Difference between revisions
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New page: left|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'' | ||
