1m52
From Proteopedia
(New page: 200px<br /><applet load="1m52" size="450" color="white" frame="true" align="right" spinBox="true" caption="1m52, resolution 2.60Å" /> '''Crystal Structure of...) |
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| - | [[Image:1m52.gif|left|200px]]<br /><applet load="1m52" size=" | + | [[Image:1m52.gif|left|200px]]<br /><applet load="1m52" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1m52, resolution 2.60Å" /> | caption="1m52, resolution 2.60Å" /> | ||
'''Crystal Structure of the c-Abl Kinase domain in complex with PD173955'''<br /> | '''Crystal Structure of the c-Abl Kinase domain in complex with PD173955'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The inadvertent fusion of the bcr gene with the abl gene results in a | + | The inadvertent fusion of the bcr gene with the abl gene results in a constitutively active tyrosine kinase (Bcr-Abl) that transforms cells and causes chronic myelogenous leukemia. Small molecule inhibitors of Bcr-Abl that bind to the kinase domain can be used to treat chronic myelogenous leukemia. We report crystal structures of the kinase domain of Abl in complex with two such inhibitors, imatinib (also known as STI-571 and Gleevec) and PD173955 (Parke-Davis). Both compounds bind to the canonical ATP-binding site of the kinase domain, but they do so in different ways. As shown previously in a crystal structure of Abl bound to a smaller variant of STI-571, STI-571 captures a specific inactive conformation of the activation loop of Abl in which the loop mimics bound peptide substrate. In contrast, PD173955 binds to a conformation of Abl in which the activation loop resembles that of an active kinase. The structure suggests that PD173955 would be insensitive to whether the conformation of the activation loop corresponds to active kinases or to that seen in the STI-571 complex. In vitro kinase assays confirm that this is the case and indicate that PD173955 is at least 10-fold more inhibitory than STI-571. The structures suggest that PD173955 achieves its greater potency over STI-571 by being able to target multiple forms of Abl (active or inactive), whereas STI-571 requires a specific inactive conformation of Abl. |
==About this Structure== | ==About this Structure== | ||
| - | 1M52 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with MES and P17 as [http://en.wikipedia.org/wiki/ligands ligands]. 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:// | + | 1M52 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=MES:'>MES</scene> and <scene name='pdbligand=P17:'>P17</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. 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=1M52 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Clarkson, B.]] | [[Category: Clarkson, B.]] | ||
[[Category: Kuriyan, J.]] | [[Category: Kuriyan, J.]] | ||
| - | [[Category: Miller, W | + | [[Category: Miller, W T.]] |
[[Category: Nagar, B.]] | [[Category: Nagar, B.]] | ||
[[Category: Pellicena, P.]] | [[Category: Pellicena, P.]] | ||
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[[Category: pd173955]] | [[Category: pd173955]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:51:34 2008'' |
Revision as of 11:51, 21 February 2008
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Crystal Structure of the c-Abl Kinase domain in complex with PD173955
Overview
The inadvertent fusion of the bcr gene with the abl gene results in a constitutively active tyrosine kinase (Bcr-Abl) that transforms cells and causes chronic myelogenous leukemia. Small molecule inhibitors of Bcr-Abl that bind to the kinase domain can be used to treat chronic myelogenous leukemia. We report crystal structures of the kinase domain of Abl in complex with two such inhibitors, imatinib (also known as STI-571 and Gleevec) and PD173955 (Parke-Davis). Both compounds bind to the canonical ATP-binding site of the kinase domain, but they do so in different ways. As shown previously in a crystal structure of Abl bound to a smaller variant of STI-571, STI-571 captures a specific inactive conformation of the activation loop of Abl in which the loop mimics bound peptide substrate. In contrast, PD173955 binds to a conformation of Abl in which the activation loop resembles that of an active kinase. The structure suggests that PD173955 would be insensitive to whether the conformation of the activation loop corresponds to active kinases or to that seen in the STI-571 complex. In vitro kinase assays confirm that this is the case and indicate that PD173955 is at least 10-fold more inhibitory than STI-571. The structures suggest that PD173955 achieves its greater potency over STI-571 by being able to target multiple forms of Abl (active or inactive), whereas STI-571 requires a specific inactive conformation of Abl.
About this Structure
1M52 is a Single protein structure of sequence from Mus musculus with and as ligands. 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
Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571)., Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J, Cancer Res. 2002 Aug 1;62(15):4236-43. PMID:12154025
Page seeded by OCA on Thu Feb 21 13:51:34 2008
Categories: Mus musculus | Single protein | Transferase | Bornmann, W. | Clarkson, B. | Kuriyan, J. | Miller, W T. | Nagar, B. | Pellicena, P. | Schindler, T. | Veach, D. | MES | P17 | Activation loop | Kinase | Kinase inhibitor | Pd173955
