2gs7: Difference between revisions
New page: left|200px<br /> <applet load="2gs7" size="450" color="white" frame="true" align="right" spinBox="true" caption="2gs7, resolution 2.600Å" /> '''Crystal Structure ... |
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[[Image:2gs7.gif|left|200px]]<br /> | [[Image:2gs7.gif|left|200px]]<br /><applet load="2gs7" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2gs7, resolution 2.600Å" /> | caption="2gs7, resolution 2.600Å" /> | ||
'''Crystal Structure of the inactive EGFR kinase domain in complex with AMP-PNP'''<br /> | '''Crystal Structure of the inactive EGFR kinase domain in complex with AMP-PNP'''<br /> | ||
==Overview== | ==Overview== | ||
The mechanism by which the epidermal growth factor receptor (EGFR) is | The mechanism by which the epidermal growth factor receptor (EGFR) is activated upon dimerization has eluded definition. We find that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine (L834R) in the activation loop, the phosphorylation of which is not required for activation. This suggests that the kinase domain is intrinsically autoinhibited, and an intermolecular interaction promotes its activation. Using further mutational analysis and crystallography we demonstrate that the autoinhibited conformation of the EGFR kinase domain resembles that of Src and cyclin-dependent kinases (CDKs). EGFR activation results from the formation of an asymmetric dimer in which the C-terminal lobe of one kinase domain plays a role analogous to that of cyclin in activated CDK/cyclin complexes. The CDK/cyclin-like complex formed by two kinase domains thus explains the activation of EGFR-family receptors by homo- or heterodimerization. | ||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
2GS7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with MG, IOD and ANP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http:// | 2GS7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=IOD:'>IOD</scene> and <scene name='pdbligand=ANP:'>ANP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GS7 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Receptor protein-tyrosine kinase]] | [[Category: Receptor protein-tyrosine kinase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Cole, P | [[Category: Cole, P A.]] | ||
[[Category: Gureasko, J.]] | [[Category: Gureasko, J.]] | ||
[[Category: Kuriyan, J.]] | [[Category: Kuriyan, J.]] | ||
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[[Category: kinase]] | [[Category: kinase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:34:44 2008'' | ||
Revision as of 18:34, 21 February 2008
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Crystal Structure of the inactive EGFR kinase domain in complex with AMP-PNP
OverviewOverview
The mechanism by which the epidermal growth factor receptor (EGFR) is activated upon dimerization has eluded definition. We find that the EGFR kinase domain can be activated by increasing its local concentration or by mutating a leucine (L834R) in the activation loop, the phosphorylation of which is not required for activation. This suggests that the kinase domain is intrinsically autoinhibited, and an intermolecular interaction promotes its activation. Using further mutational analysis and crystallography we demonstrate that the autoinhibited conformation of the EGFR kinase domain resembles that of Src and cyclin-dependent kinases (CDKs). EGFR activation results from the formation of an asymmetric dimer in which the C-terminal lobe of one kinase domain plays a role analogous to that of cyclin in activated CDK/cyclin complexes. The CDK/cyclin-like complex formed by two kinase domains thus explains the activation of EGFR-family receptors by homo- or heterodimerization.
DiseaseDisease
Known diseases associated with this structure: Adenocarcinoma of lung, response to tyrosine kinase inhibitor in OMIM:[131550], Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in OMIM:[131550], Nonsmall cell lung cancer, susceptibility to OMIM:[131550]
About this StructureAbout this Structure
2GS7 is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Full crystallographic information is available from OCA.
ReferenceReference
An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor., Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J, Cell. 2006 Jun 16;125(6):1137-49. PMID:16777603
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