2g2h
From Proteopedia
(New page: 200px<br /> <applet load="2g2h" size="450" color="white" frame="true" align="right" spinBox="true" caption="2g2h, resolution 2.0Å" /> '''A Src-like Inactive ...) |
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| - | [[Image:2g2h.gif|left|200px]]<br /> | + | [[Image:2g2h.gif|left|200px]]<br /><applet load="2g2h" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="2g2h, resolution 2.0Å" /> | caption="2g2h, resolution 2.0Å" /> | ||
'''A Src-like Inactive Conformation in the Abl Tyrosine Kinase Domain'''<br /> | '''A Src-like Inactive Conformation in the Abl Tyrosine Kinase Domain'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The improper activation of the Abl tyrosine kinase results in chronic | + | The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP-peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR-Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2G2H 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 P16 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 2G2H 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=P16:'>P16</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G2H OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Kuchment, O.]] | [[Category: Kuchment, O.]] | ||
| - | [[Category: Levinson, N | + | [[Category: Levinson, N M.]] |
[[Category: P16]] | [[Category: P16]] | ||
[[Category: protein kinase]] | [[Category: protein kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:27:28 2008'' |
Revision as of 15:27, 21 February 2008
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A Src-like Inactive Conformation in the Abl Tyrosine Kinase Domain
Contents |
Overview
The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP-peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR-Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain.
Disease
Known diseases associated with this structure: Leukemia, Philadelphia chromosome-positive, resistant to imatinib OMIM:[189980]
About this Structure
2G2H is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
Reference
A Src-like inactive conformation in the abl tyrosine kinase domain., Levinson NM, Kuchment O, Shen K, Young MA, Koldobskiy M, Karplus M, Cole PA, Kuriyan J, PLoS Biol. 2006 May;4(5):e144. Epub 2006 May 2. PMID:16640460
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