2qlq: Difference between revisions

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Revision as of 19:27, 20 March 2008

File:2qlq.jpg

, resolution 2.33Å

Sites:

, and

Ligands:

Gene:

SRC (Gallus gallus)

Activity:

Non-specific protein-tyrosine kinase, with EC number 2.7.10.2

Coordinates:

save as pdb, mmCIF, xml

Crystal structure of src kinase with covalent inhibitor XXX

OverviewOverview

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 StructureAbout this Structure

2QLQ is a Single protein structure of sequence from Gallus gallus. Full crystallographic information is available from OCA.

ReferenceReference

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:18316192

Page seeded by OCA on Thu Mar 20 18:27:06 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:2qlq.jpg|left|200px]]<br /><applet load="2qlq" size="350" color="white" frame="true" align="right" spinBox="true"
+[[Image:2qlq.jpg|left|200px]]
-caption="2qlq, resolution 2.33&Aring;" />
-'''Crystal structure of src kinase with covalent inhibitor XXX'''<br />
+ {{Structure
+|PDB= 2qlq |SIZE=350|CAPTION= <scene name='initialview01'>2qlq</scene>, resolution 2.33&Aring;
+|SITE= <scene name='pdbsite=AC1:Sr2+Binding+Site+For+Residue+A+1345'>AC1</scene>, <scene name='pdbsite=AC2:Sr2+Binding+Site+For+Residue+A+1483'>AC2</scene> and <scene name='pdbsite=AC3:Sr2+Binding+Site+For+Residue+B+1345'>AC3</scene>
+|LIGAND= <scene name='pdbligand=SR2:'>SR2</scene>
+|ACTIVITY= [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]
+|GENE= SRC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9031 Gallus gallus])
+}}
+'''Crystal structure of src kinase with covalent inhibitor XXX'''
 ==Overview==
@@ Line 7: / Line 16: @@
 ==About this Structure==
-QLQ 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>, <scene name='pdbsite=AC2:Sr2+Binding+Site+For+Residue+A+1483'>AC2</scene> and <scene name='pdbsite=AC3:Sr2+Binding+Site+For+Residue+B+1345'>AC3</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QLQ OCA].
+QLQ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2QLQ 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]
+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://www.ncbi.nlm.nih.gov/pubmed/18316192 18316192]
 [[Category: Gallus gallus]]
 [[Category: Non-specific protein-tyrosine kinase]]
@@ Line 35: / Line 44: @@
 [[Category: tyrosine-protein kinase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Mar 14 09:34:45 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:27:06 2008''