1yy9
From Proteopedia
(New page: 200px<br /> <applet load="1yy9" size="450" color="white" frame="true" align="right" spinBox="true" caption="1yy9, resolution 2.605Å" /> '''Structure of the e...) |
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| - | [[Image:1yy9.gif|left|200px]]<br /> | + | [[Image:1yy9.gif|left|200px]]<br /><applet load="1yy9" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1yy9" size=" | + | |
caption="1yy9, resolution 2.605Å" /> | caption="1yy9, resolution 2.605Å" /> | ||
'''Structure of the extracellular domain of the epidermal growth factor receptor in complex with the Fab fragment of cetuximab/Erbitux/IMC-C225'''<br /> | '''Structure of the extracellular domain of the epidermal growth factor receptor in complex with the Fab fragment of cetuximab/Erbitux/IMC-C225'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Recent structural studies of epidermal growth factor receptor (EGFR) | + | Recent structural studies of epidermal growth factor receptor (EGFR) family extracellular regions have identified an unexpected mechanism for ligand-induced receptor dimerization that has important implications for activation and inhibition of these receptors. Here we describe the 2.8 angstroms resolution X-ray crystal structure of the antigen binding (Fab) fragment from cetuximab (Erbitux), an inhibitory anti-EGFR antibody, in complex with the soluble extracellular region of EGFR (sEGFR). The sEGFR is in the characteristic "autoinhibited" or "tethered" inactive configuration. Cetuximab interacts exclusively with domain III of sEGFR, partially occluding the ligand binding region on this domain and sterically preventing the receptor from adopting the extended conformation required for dimerization. We suggest that both these effects contribute to potent inhibition of EGFR activation. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1YY9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus/homo_sapiens Mus musculus/homo sapiens] with NDG and NAG 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:// | + | 1YY9 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus/homo_sapiens Mus musculus/homo sapiens] with <scene name='pdbligand=NDG:'>NDG</scene> and <scene name='pdbligand=NAG:'>NAG</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=1YY9 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
| - | [[Category: Ferguson, K | + | [[Category: Ferguson, K M.]] |
| - | [[Category: Jeffrey, P | + | [[Category: Jeffrey, P D.]] |
[[Category: Kussie, P.]] | [[Category: Kussie, P.]] | ||
[[Category: Li, S.]] | [[Category: Li, S.]] | ||
| - | [[Category: Schmitz, K | + | [[Category: Schmitz, K R.]] |
| - | [[Category: Wiltzius, J | + | [[Category: Wiltzius, J J.W.]] |
[[Category: NAG]] | [[Category: NAG]] | ||
[[Category: NDG]] | [[Category: NDG]] | ||
[[Category: cell surface receptor; tyrosine kinase; glycoprotein; antigen:antibody complex; fab fragment; antitumor; drug]] | [[Category: cell surface receptor; tyrosine kinase; glycoprotein; antigen:antibody complex; fab fragment; antitumor; drug]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:10:21 2008'' |
Revision as of 14:10, 21 February 2008
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Structure of the extracellular domain of the epidermal growth factor receptor in complex with the Fab fragment of cetuximab/Erbitux/IMC-C225
Contents |
Overview
Recent structural studies of epidermal growth factor receptor (EGFR) family extracellular regions have identified an unexpected mechanism for ligand-induced receptor dimerization that has important implications for activation and inhibition of these receptors. Here we describe the 2.8 angstroms resolution X-ray crystal structure of the antigen binding (Fab) fragment from cetuximab (Erbitux), an inhibitory anti-EGFR antibody, in complex with the soluble extracellular region of EGFR (sEGFR). The sEGFR is in the characteristic "autoinhibited" or "tethered" inactive configuration. Cetuximab interacts exclusively with domain III of sEGFR, partially occluding the ligand binding region on this domain and sterically preventing the receptor from adopting the extended conformation required for dimerization. We suggest that both these effects contribute to potent inhibition of EGFR activation.
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
1YY9 is a Single protein structure of sequence from Homo sapiens and Mus musculus/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
Structural basis for inhibition of the epidermal growth factor receptor by cetuximab., Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM, Cancer Cell. 2005 Apr;7(4):301-11. PMID:15837620
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