2hwo
From Proteopedia
(New page: 200px<br /><applet load="2hwo" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hwo, resolution 2.500Å" /> '''Crystal structure o...) |
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| - | [[Image:2hwo.jpg|left|200px]]<br /><applet load="2hwo" size=" | + | [[Image:2hwo.jpg|left|200px]]<br /><applet load="2hwo" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2hwo, resolution 2.500Å" /> | caption="2hwo, resolution 2.500Å" /> | ||
'''Crystal structure of Src kinase domain in complex with covalent inhibitor'''<br /> | '''Crystal structure of Src kinase domain in complex with covalent inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | As key components in nearly every signal transduction pathway, protein | + | As key components in nearly every signal transduction pathway, protein kinases are attractive targets for the regulation of cellular signaling by small-molecule inhibitors. We report the structure-guided development of 6-acrylamido-4-anilinoquinazoline irreversible kinase inhibitors that potently and selectively target rationally designed kinases bearing two selectivity elements that are not found together in any wild-type kinase: an electrophile-targeted cysteine residue and a glycine gatekeeper residue. Cocrystal structures of two irreversible quinazoline inhibitors bound to either epidermal growth factor receptor (EGFR) or engineered c-Src show covalent inhibitor binding to the targeted cysteine (Cys797 in EGFR and Cys345 in engineered c-Src). To accommodate the new covalent bond, the quinazoline core adopts positions that are different from those seen in kinase structures with reversible quinazoline inhibitors. Based on these structures, we developed a fluorescent 6-acrylamido-4-anilinoquinazoline affinity probe to report the fraction of kinase necessary for cellular signaling, and we used these reagents to quantitate the relationship between EGFR stimulation by EGF and its downstream outputs-Akt, Erk1 and Erk2. |
==About this Structure== | ==About this Structure== | ||
| - | 2HWO 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 RBS 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:// | + | 2HWO 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=RBS:'>RBS</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=2HWO OCA]. |
==Reference== | ==Reference== | ||
| - | Structure-guided development of affinity probes for tyrosine kinases using chemical genetics., Blair JA, Rauh D, Kung C, Yun CH, Fan QW, Rode H, Zhang C, Eck MJ, Weiss WA, Shokat KM, Nat Chem Biol. 2007 Apr;3(4):229- | + | Structure-guided development of affinity probes for tyrosine kinases using chemical genetics., Blair JA, Rauh D, Kung C, Yun CH, Fan QW, Rode H, Zhang C, Eck MJ, Weiss WA, Shokat KM, Nat Chem Biol. 2007 Apr;3(4):229-38. Epub 2007 Mar 4. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17334377 17334377] |
[[Category: Gallus gallus]] | [[Category: Gallus gallus]] | ||
[[Category: Non-specific protein-tyrosine kinase]] | [[Category: Non-specific protein-tyrosine kinase]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Blair, J | + | [[Category: Blair, J A.]] |
[[Category: Rauh, D.]] | [[Category: Rauh, D.]] | ||
| - | [[Category: Shokat, K | + | [[Category: Shokat, K M.]] |
[[Category: GOL]] | [[Category: GOL]] | ||
[[Category: RBS]] | [[Category: RBS]] | ||
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[[Category: quinazoline]] | [[Category: quinazoline]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:46:47 2008'' |
Revision as of 15:46, 21 February 2008
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Crystal structure of Src kinase domain in complex with covalent inhibitor
Overview
As key components in nearly every signal transduction pathway, protein kinases are attractive targets for the regulation of cellular signaling by small-molecule inhibitors. We report the structure-guided development of 6-acrylamido-4-anilinoquinazoline irreversible kinase inhibitors that potently and selectively target rationally designed kinases bearing two selectivity elements that are not found together in any wild-type kinase: an electrophile-targeted cysteine residue and a glycine gatekeeper residue. Cocrystal structures of two irreversible quinazoline inhibitors bound to either epidermal growth factor receptor (EGFR) or engineered c-Src show covalent inhibitor binding to the targeted cysteine (Cys797 in EGFR and Cys345 in engineered c-Src). To accommodate the new covalent bond, the quinazoline core adopts positions that are different from those seen in kinase structures with reversible quinazoline inhibitors. Based on these structures, we developed a fluorescent 6-acrylamido-4-anilinoquinazoline affinity probe to report the fraction of kinase necessary for cellular signaling, and we used these reagents to quantitate the relationship between EGFR stimulation by EGF and its downstream outputs-Akt, Erk1 and Erk2.
About this Structure
2HWO 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
Structure-guided development of affinity probes for tyrosine kinases using chemical genetics., Blair JA, Rauh D, Kung C, Yun CH, Fan QW, Rode H, Zhang C, Eck MJ, Weiss WA, Shokat KM, Nat Chem Biol. 2007 Apr;3(4):229-38. Epub 2007 Mar 4. PMID:17334377
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