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2hiw
From Proteopedia
(New page: 200px<br /> <applet load="2hiw" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hiw, resolution 2.20Å" /> '''Crystal Structure o...) |
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| - | [[Image:2hiw.gif|left|200px]]<br /> | + | [[Image:2hiw.gif|left|200px]]<br /><applet load="2hiw" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2hiw" size=" | + | |
caption="2hiw, resolution 2.20Å" /> | caption="2hiw, resolution 2.20Å" /> | ||
'''Crystal Structure of Inactive Conformation Abl Kinase Catalytic Domain Complexed with Type II Inhibitor'''<br /> | '''Crystal Structure of Inactive Conformation Abl Kinase Catalytic Domain Complexed with Type II Inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Kinase inhibitors that bind to the ATP cleft can be broadly classified | + | Kinase inhibitors that bind to the ATP cleft can be broadly classified into two groups: those that bind exclusively to the ATP site with the kinase assuming a conformation otherwise conducive to phosphotransfer (type I), and those that exploit a hydrophobic site immediately adjacent to the ATP pocket made accessible by a conformational rearrangement of the activation loop (type II). To date, all type II inhibitors were discovered by using structure-activity-guided optimization strategies. Here, we describe a general pharmacophore model of type II inhibition that enables a rational "hybrid-design" approach whereby a 3-trifluoromethylbenzamide functionality is appended to four distinct type I scaffolds in order to convert them into their corresponding type II counterparts. We demonstrate that the designed compounds function as type II inhibitors by using biochemical and cellular kinase assays and by cocrystallography with Abl. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2HIW 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 7MP as [http://en.wikipedia.org/wiki/ligand ligand]. 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:// | + | 2HIW 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=7MP:'>7MP</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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=2HIW OCA]. |
==Reference== | ==Reference== | ||
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[[Category: kinase domain]] | [[Category: kinase domain]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:42:23 2008'' |
Revision as of 15:42, 21 February 2008
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Crystal Structure of Inactive Conformation Abl Kinase Catalytic Domain Complexed with Type II Inhibitor
Contents |
Overview
Kinase inhibitors that bind to the ATP cleft can be broadly classified into two groups: those that bind exclusively to the ATP site with the kinase assuming a conformation otherwise conducive to phosphotransfer (type I), and those that exploit a hydrophobic site immediately adjacent to the ATP pocket made accessible by a conformational rearrangement of the activation loop (type II). To date, all type II inhibitors were discovered by using structure-activity-guided optimization strategies. Here, we describe a general pharmacophore model of type II inhibition that enables a rational "hybrid-design" approach whereby a 3-trifluoromethylbenzamide functionality is appended to four distinct type I scaffolds in order to convert them into their corresponding type II counterparts. We demonstrate that the designed compounds function as type II inhibitors by using biochemical and cellular kinase assays and by cocrystallography with Abl.
Disease
Known diseases associated with this structure: Leukemia, Philadelphia chromosome-positive, resistant to imatinib OMIM:[189980]
About this Structure
2HIW is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Full crystallographic information is available from OCA.
Reference
A general strategy for creating "inactive-conformation" abl inhibitors., Okram B, Nagle A, Adrian FJ, Lee C, Ren P, Wang X, Sim T, Xie Y, Wang X, Xia G, Spraggon G, Warmuth M, Liu Y, Gray NS, Chem Biol. 2006 Jul;13(7):779-86. PMID:16873026
Page seeded by OCA on Thu Feb 21 17:42:23 2008
