1xkk
From Proteopedia
(New page: 200px<br /> <applet load="1xkk" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xkk, resolution 2.40Å" /> '''EGFR kinase domain ...) |
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| - | [[Image:1xkk.gif|left|200px]]<br /> | + | [[Image:1xkk.gif|left|200px]]<br /><applet load="1xkk" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1xkk" size=" | + | |
caption="1xkk, resolution 2.40Å" /> | caption="1xkk, resolution 2.40Å" /> | ||
'''EGFR kinase domain complexed with a quinazoline inhibitor- GW572016'''<br /> | '''EGFR kinase domain complexed with a quinazoline inhibitor- GW572016'''<br /> | ||
==Overview== | ==Overview== | ||
| - | GW572016 (Lapatinib) is a tyrosine kinase inhibitor in clinical | + | 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. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1XKK 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 PO4 and FMM as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http:// | + | 1XKK 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=PO4:'>PO4</scene> and <scene name='pdbligand=FMM:'>FMM</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XKK OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
| - | [[Category: Alligood, K | + | [[Category: Alligood, K J.]] |
| - | [[Category: Dickerson, S | + | [[Category: Dickerson, S H.]] |
[[Category: Ellis, B.]] | [[Category: Ellis, B.]] | ||
| - | [[Category: Gilmer, T | + | [[Category: Gilmer, T M.]] |
[[Category: Hassell, A.]] | [[Category: Hassell, A.]] | ||
[[Category: Horne, E.]] | [[Category: Horne, E.]] | ||
[[Category: Lackey, K.]] | [[Category: Lackey, K.]] | ||
| - | [[Category: McDonald, O | + | [[Category: McDonald, O B.]] |
[[Category: Pennisi, C.]] | [[Category: Pennisi, C.]] | ||
| - | [[Category: Rusnak, D | + | [[Category: Rusnak, D W.]] |
| - | [[Category: Shewchuk, L | + | [[Category: Shewchuk, L M.]] |
| - | [[Category: Truesdale, A | + | [[Category: Truesdale, A T.]] |
| - | [[Category: Wood, E | + | [[Category: Wood, E R.]] |
[[Category: Yuan, D.]] | [[Category: Yuan, D.]] | ||
[[Category: FMM]] | [[Category: FMM]] | ||
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[[Category: kinase]] | [[Category: kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:55:45 2008'' |
Revision as of 13:55, 21 February 2008
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EGFR kinase domain complexed with a quinazoline inhibitor- GW572016
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Adenocarcinoma of lung, response to tyrosine kinase inhibitor in OMIM:[131550], Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in OMIM:[131550], Nonsmall cell lung cancer, susceptibility to OMIM:[131550]
About this Structure
1XKK is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 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 Thu Feb 21 15:55:45 2008
Categories: Homo sapiens | Single protein | Transferase | Alligood, K J. | Dickerson, S H. | Ellis, B. | Gilmer, T M. | Hassell, A. | Horne, E. | Lackey, K. | McDonald, O B. | Pennisi, C. | Rusnak, D W. | Shewchuk, L M. | Truesdale, A T. | Wood, E R. | Yuan, D. | FMM | PO4 | Egfr | Epidermal growth factor receptor | Kinase
