2r4b

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{{STRUCTURE_2r4b| PDB=2r4b | SCENE= }}
{{STRUCTURE_2r4b| PDB=2r4b | SCENE= }}
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'''ErbB4 kinase domain complexed with a thienopyrimidine inhibitor'''
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===ErbB4 kinase domain complexed with a thienopyrimidine inhibitor===
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==Overview==
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Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.
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(as it appears on PubMed at http://www.pubmed.gov), where 18287036 is the PubMed ID number.
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{{ABSTRACT_PUBMED_18287036}}
==About this Structure==
==About this Structure==
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[[Category: Transmembrane]]
[[Category: Transmembrane]]
[[Category: Tyrosine-protein kinase]]
[[Category: Tyrosine-protein kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 16:13:17 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 05:10:30 2008''

Revision as of 02:10, 28 July 2008

Image:2r4b.png

Template:STRUCTURE 2r4b

ErbB4 kinase domain complexed with a thienopyrimidine inhibitor

Template:ABSTRACT PUBMED 18287036

About this Structure

2R4B is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases., Wood ER, Shewchuk LM, Ellis B, Brignola P, Brashear RL, Caferro TR, Dickerson SH, Dickson HD, Donaldson KH, Gaul M, Griffin RJ, Hassell AM, Keith B, Mullin R, Petrov KG, Reno MJ, Rusnak DW, Tadepalli SM, Ulrich JC, Wagner CD, Vanderwall DE, Waterson AG, Williams JD, White WL, Uehling DE, Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2773-8. Epub 2008 Feb 19. PMID:18287036

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