2oiq
From Proteopedia
(New page: 200px<br /><applet load="2oiq" size="450" color="white" frame="true" align="right" spinBox="true" caption="2oiq, resolution 2.07Å" /> '''Crystal Structure of...) |
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| - | [[Image:2oiq.gif|left|200px]]<br /><applet load="2oiq" size=" | + | [[Image:2oiq.gif|left|200px]]<br /><applet load="2oiq" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2oiq, resolution 2.07Å" /> | caption="2oiq, resolution 2.07Å" /> | ||
'''Crystal Structure of chicken c-Src kinase domain in complex with the cancer drug imatinib.'''<br /> | '''Crystal Structure of chicken c-Src kinase domain in complex with the cancer drug imatinib.'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The cancer drug imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and | + | The cancer drug imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and the PDGF receptor. Imatinib is less effective against c-Src, which is difficult to understand because residues interacting with imatinib in crystal structures of Abl and c-Kit are conserved in c-Src. The crystal structure of the c-Src kinase domain in complex with imatinib closely resembles that of Abl*imatinib and c-Kit*imatinib, and differs significantly from the inactive "Src/CDK" conformation of the Src family kinases. Attempts to increase the affinity of c-Src for imatinib by swapping residues with the corresponding residues in Abl have not been successful, suggesting that the thermodynamic penalty for adoption of the imatinib-binding conformation by c-Src is distributed over a broad region of the structure. Two mutations that are expected to destabilize the inactive Src/CDK conformation increase drug sensitivity 15-fold, suggesting that the free-energy balance between different inactive states is a key to imatinib binding. |
==About this Structure== | ==About this Structure== | ||
| - | 2OIQ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] with STI and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] Full crystallographic information is available from [http:// | + | 2OIQ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] with <scene name='pdbligand=STI:'>STI</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OIQ OCA]. |
==Reference== | ==Reference== | ||
| - | c-Src | + | c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty., Seeliger MA, Nagar B, Frank F, Cao X, Henderson MN, Kuriyan J, Structure. 2007 Mar;15(3):299-311. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17355866 17355866] |
[[Category: Gallus gallus]] | [[Category: Gallus gallus]] | ||
[[Category: Non-specific protein-tyrosine kinase]] | [[Category: Non-specific protein-tyrosine kinase]] | ||
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[[Category: Cao, X.]] | [[Category: Cao, X.]] | ||
[[Category: Frank, F.]] | [[Category: Frank, F.]] | ||
| - | [[Category: Henderson, M | + | [[Category: Henderson, M N.]] |
[[Category: Kuriyan, J.]] | [[Category: Kuriyan, J.]] | ||
[[Category: Nagar, B.]] | [[Category: Nagar, B.]] | ||
| - | [[Category: Seeliger, M | + | [[Category: Seeliger, M A.]] |
[[Category: GOL]] | [[Category: GOL]] | ||
[[Category: STI]] | [[Category: STI]] | ||
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[[Category: src]] | [[Category: src]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:19:00 2008'' |
Revision as of 16:19, 21 February 2008
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Crystal Structure of chicken c-Src kinase domain in complex with the cancer drug imatinib.
Overview
The cancer drug imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and the PDGF receptor. Imatinib is less effective against c-Src, which is difficult to understand because residues interacting with imatinib in crystal structures of Abl and c-Kit are conserved in c-Src. The crystal structure of the c-Src kinase domain in complex with imatinib closely resembles that of Abl*imatinib and c-Kit*imatinib, and differs significantly from the inactive "Src/CDK" conformation of the Src family kinases. Attempts to increase the affinity of c-Src for imatinib by swapping residues with the corresponding residues in Abl have not been successful, suggesting that the thermodynamic penalty for adoption of the imatinib-binding conformation by c-Src is distributed over a broad region of the structure. Two mutations that are expected to destabilize the inactive Src/CDK conformation increase drug sensitivity 15-fold, suggesting that the free-energy balance between different inactive states is a key to imatinib binding.
About this Structure
2OIQ is a Single protein structure of sequence from Gallus gallus with and as ligands. Active as Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Full crystallographic information is available from OCA.
Reference
c-Src binds to the cancer drug imatinib with an inactive Abl/c-Kit conformation and a distributed thermodynamic penalty., Seeliger MA, Nagar B, Frank F, Cao X, Henderson MN, Kuriyan J, Structure. 2007 Mar;15(3):299-311. PMID:17355866
Page seeded by OCA on Thu Feb 21 18:19:00 2008
Categories: Gallus gallus | Non-specific protein-tyrosine kinase | Single protein | Cao, X. | Frank, F. | Henderson, M N. | Kuriyan, J. | Nagar, B. | Seeliger, M A. | GOL | STI | Imatinib | Inactive | Kinase | Src
