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1xkk

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[[Image:1xkk.gif|left|200px]]
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{{STRUCTURE_1xkk| PDB=1xkk | SCENE= }}
{{STRUCTURE_1xkk| PDB=1xkk | SCENE= }}
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'''EGFR kinase domain complexed with a quinazoline inhibitor- GW572016'''
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===EGFR kinase domain complexed with a quinazoline inhibitor- GW572016===
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==Overview==
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GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor (EGFR, ErbB-1) and ErbB-2. We determined the crystal structure of EGFR bound to GW572016. The compound is bound to an inactive-like conformation of EGFR that is very different from the active-like structure bound by the selective EGFR inhibitor OSI-774 (Tarceva) described previously. Surprisingly, we found that GW572016 has a very slow off-rate from the purified intracellular domains of EGFR and ErbB-2 compared with OSI-774 and another EGFR selective inhibitor, ZD-1839 (Iressa). Treatment of tumor cells with these inhibitors results in down-regulation of receptor tyrosine phosphorylation. We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off-rate from the purified intracellular domain. The slow off-rate of GW572016 correlates with a prolonged down-regulation of receptor tyrosine phosphorylation in tumor cells. The differences in the off-rates of these drugs and the ability of GW572016 to inhibit ErbB-2 can be explained by the enzyme-inhibitor structures.
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The line below this paragraph, {{ABSTRACT_PUBMED_15374980}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 15374980 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15374980}}
==About this Structure==
==About this Structure==
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[[Category: Epidermal growth factor receptor]]
[[Category: Epidermal growth factor receptor]]
[[Category: Kinase]]
[[Category: Kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 15:08:44 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 11:18:48 2008''

Revision as of 08:18, 29 July 2008

Image:1xkk.png

Template:STRUCTURE 1xkk

EGFR kinase domain complexed with a quinazoline inhibitor- GW572016

Template:ABSTRACT PUBMED 15374980

About this Structure

1XKK is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells., Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L, Cancer Res. 2004 Sep 15;64(18):6652-9. PMID:15374980

Page seeded by OCA on Tue Jul 29 11:18:48 2008

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