2j5e: Difference between revisions
New page: left|200px<br /> <applet load="2j5e" size="450" color="white" frame="true" align="right" spinBox="true" caption="2j5e, resolution 3.10Å" /> '''CRYSTAL STRUCTURE O... |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:2j5e. | [[Image:2j5e.jpg|left|200px]]<br /><applet load="2j5e" size="350" color="white" frame="true" align="right" spinBox="true" | ||
<applet load="2j5e" size=" | |||
caption="2j5e, resolution 3.10Å" /> | caption="2j5e, resolution 3.10Å" /> | ||
'''CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN IN COMPLEX WITH AN IRREVERSIBLE INHIBITOR 13-JAB'''<br /> | '''CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN IN COMPLEX WITH AN IRREVERSIBLE INHIBITOR 13-JAB'''<br /> | ||
| Line 6: | Line 5: | ||
==Overview== | ==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. | 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== | ||
2J5E 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 CL as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http:// | 2J5E 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=CL:'>CL</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2J5E OCA]. | ||
==Reference== | ==Reference== | ||
| Line 43: | Line 39: | ||
[[Category: wild-type]] | [[Category: wild-type]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 14:28:29 2008'' | ||
Revision as of 15:28, 23 January 2008
|
CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN IN COMPLEX WITH AN IRREVERSIBLE INHIBITOR 13-JAB
OverviewOverview
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 StructureAbout this Structure
2J5E is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Full crystallographic information is available from OCA.
ReferenceReference
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):229-238. Epub 2007 Mar 4. PMID:17334377
Page seeded by OCA on Wed Jan 23 14:28:29 2008
Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Receptor protein-tyrosine kinase
- Single protein
- Eck, M.J.
- Yun, C.H.
- CL
- 13-jab
- Alternative splicing
- Anti-oncogene
- Atp-binding
- Cell cycle
- Disease mutation
- Egfr
- Epidermal growth factor
- Glycoprotein
- Irreversible inhibitor
- Kinase
- Membrane
- Nucleotide-binding
- Phosphorylation
- Polymorphism
- Receptor
- Transferase
- Transmembrane
- Tyrosine-protein kinase
- Ubl conjugation
- Wild-type