View source for 2qq7

[[Image:2qq7.jpg|left|200px]]<br /><applet load="2qq7" size="350" color="white" frame="true" align="right" spinBox="true" 
caption="2qq7, resolution 2.380&Aring;" />
'''Crystal structure of drug resistant SRC kinase domain with irreversible inhibitor'''<br />

==Overview==
Resistance to kinase- targeted cancer drugs has recently been linked to a single point mutation in the ATP binding site of the kinase. In EGFR, the crucial Thr790 gatekeeper residue is mutated to a Met and prevents reversible ATP competitive inhibitors from binding. Irreversible 4-(phenylamino)quinazolines have been shown to overcome this drug resistance and are currently in clinical trials. In order to obtain a detailed structural understanding of how irreversible inhibitors overcome drug resistance, we used Src kinase as a model system for drug resistant EGFR-T790M. We report the first crystal structure of a drug resistant kinase in complex with an irreversible inhibitor. This 4-(phenylamino)quinazoline inhibits wild type and drug resistant EGFR in vitro at low nM concentrations. The co-crystal structure of drug resistant cSrc-T338M kinase domain provides the structural basis of this activity.

==About this Structure==
2QQ7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus] with <scene name='pdbligand=SR2:'>SR2</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] Known structural/functional Sites: <scene name='pdbsite=AC1:Sr2+Binding+Site+For+Residue+A+1345'>AC1</scene> and <scene name='pdbsite=AC2:Sr2+Binding+Site+For+Residue+B+1345'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QQ7 OCA]. 

==Reference==
Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR., Michalczyk A, Kluter S, Rode HB, Simard JR, Grutter C, Rabiller M, Rauh D, Bioorg Med Chem. 2008 Feb 20;. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18316192 18316192]
[[Category: Gallus gallus]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Single protein]]
[[Category: Gruetter, C.]]
[[Category: Michalczyk, A.]]
[[Category: Rauh, D.]]
[[Category: Rode, H B.]]
[[Category: SR2]]
[[Category: alternative splicing]]
[[Category: atp-binding]]
[[Category: drug resistance]]
[[Category: irreversible inhibitor]]
[[Category: lipoprotein]]
[[Category: myristate]]
[[Category: nucleotide-binding]]
[[Category: phosphorylation]]
[[Category: proto-oncogene]]
[[Category: sh2 domain]]
[[Category: sh3 domain]]
[[Category: src kinase domain]]
[[Category: transferase]]
[[Category: tyrosine-protein kinase]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Mar 14 09:35:06 2008''