View source for 4ckr


==Crystal structure of the human DDR1 kinase domain in complex with DDR1-IN-1==
<StructureSection load='4ckr' size='340' side='right' caption='[[4ckr]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4ckr]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4bki 4bki]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CKR OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CKR FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DI1:4-[(4-ETHYLPIPERAZIN-1-YL)METHYL]-N-{4-METHYL-3-[(2-OXO-2,3-DIHYDRO-1H-INDOL-5-YL)OXY]PHENYL}-3-(TRIFLUOROMETHYL)BENZAMIDE'>DI1</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ckr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ckr OCA], [http://pdbe.org/4ckr PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ckr RCSB], [http://www.ebi.ac.uk/pdbsum/4ckr PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ckr ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been implicated in numerous cellular functions such as proliferation, differentiation, adhesion, migration, and invasion. Here we report the discovery of a potent and selective DDR1 inhibitor, DDR1-IN-1, and present the 2.2 A DDR1 co-crystal structure. DDR1-IN-1 binds to DDR1 in the 'DFG-out' conformation and inhibits DDR1 autophosphorylation in cells at submicromolar concentrations with good selectivity as assessed against a panel of 451 kinases measured using the KinomeScan technology. We identified a mutation in the hinge region of DDR1, G707A, that confers &gt;20-fold resistance to the ability of DDR1-IN-1 to inhibit DDR1 autophosphorylation and can be used to establish what pharmacology is DDR1-dependent. A combinatorial screen of DDR1-IN-1 with a library of annotated kinase inhibitors revealed that inhibitors of PI3K and mTOR such as GSK2126458 potentiate the antiproliferative activity of DDR1-IN-1 in colorectal cancer cell lines. DDR1-IN-1 provides a useful pharmacological probe for DDR1-dependent signal transduction.

Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitor.,Kim HG, Tan L, Weisberg EL, Liu F, Canning P, Choi HG, Ezell SA, Wu H, Zhao Z, Wang J, Mandinova A, Griffin JD, Bullock AN, Liu Q, Lee SW, Gray NS ACS Chem Biol. 2013 Oct 18;8(10):2145-50. doi: 10.1021/cb400430t. Epub 2013 Aug, 13. PMID:23899692<ref>PMID:23899692</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4ckr" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Arrowsmith, C H]]
[[Category: Bountra, C]]
[[Category: Bullock, A]]
[[Category: Canning, P]]
[[Category: Chaikuad, A]]
[[Category: Delft, F von]]
[[Category: Dixon-Clarke, S]]
[[Category: Edwards, A M]]
[[Category: Elkins, J M]]
[[Category: Goubin, S]]
[[Category: Krojer, T]]
[[Category: Mahajan, P]]
[[Category: Newman, J A]]
[[Category: Collagen]]
[[Category: Discoidin domain]]
[[Category: Transferase]]