2hog: Difference between revisions

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Revision as of 18:19, 20 March 2008

File:2hog.jpg

, resolution 1.9Å

Ligands:

Gene:

CHEK1, CHK1 (Homo sapiens)

Activity:

Non-specific serine/threonine protein kinase, with EC number 2.7.11.1

Coordinates:

save as pdb, mmCIF, xml

crystal structure of Chek1 in complex with inhibitor 20

OverviewOverview

The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC(50)=0.30nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.

About this StructureAbout this Structure

2HOG is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6., Fraley ME, Steen JT, Brnardic EJ, Arrington KL, Spencer KL, Hanney BA, Kim Y, Hartman GD, Stirdivant SM, Drakas BA, Rickert K, Walsh ES, Hamilton K, Buser CA, Hardwick J, Tao W, Beck SC, Mao X, Lobell RB, Sepp-Lorenzino L, Yan Y, Ikuta M, Munshi SK, Kuo LC, Kreatsoulas C, Bioorg Med Chem Lett. 2006 Dec 1;16(23):6049-53. Epub 2006 Sep 15. PMID:16978863

Page seeded by OCA on Thu Mar 20 17:19:29 2008

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

OCA

@@ Line 1: / Line 1: @@
-[[Image:2hog.jpg|left|200px]]<br /><applet load="2hog" size="350" color="white" frame="true" align="right" spinBox="true"
+[[Image:2hog.jpg|left|200px]]
-caption="2hog, resolution 1.9&Aring;" />
-'''crystal structure of Chek1 in complex with inhibitor 20'''<br />
+ {{Structure
+|PDB= 2hog |SIZE=350|CAPTION= <scene name='initialview01'>2hog</scene>, resolution 1.9&Aring;
+|SITE=
+|LIGAND= <scene name='pdbligand=710:(5-{3-[5-(PIPERIDIN-1-YLMETHYL)-1H-INDOL-2-YL]-1H-INDAZOL-6-YL}-2H-1,2,3-TRIAZOL-4-YL)METHANOL'>710</scene>
+|ACTIVITY= [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1]
+|GENE= CHEK1, CHK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+}}
+'''crystal structure of Chek1 in complex with inhibitor 20'''
 ==Overview==
@@ Line 7: / Line 16: @@
 ==About this Structure==
-HOG 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=710:'>710</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HOG OCA].
+HOG is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2HOG OCA].
 ==Reference==
--(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6., Fraley ME, Steen JT, Brnardic EJ, Arrington KL, Spencer KL, Hanney BA, Kim Y, Hartman GD, Stirdivant SM, Drakas BA, Rickert K, Walsh ES, Hamilton K, Buser CA, Hardwick J, Tao W, Beck SC, Mao X, Lobell RB, Sepp-Lorenzino L, Yan Y, Ikuta M, Munshi SK, Kuo LC, Kreatsoulas C, Bioorg Med Chem Lett. 2006 Dec 1;16(23):6049-53. Epub 2006 Sep 15. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16978863 16978863]
+-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6., Fraley ME, Steen JT, Brnardic EJ, Arrington KL, Spencer KL, Hanney BA, Kim Y, Hartman GD, Stirdivant SM, Drakas BA, Rickert K, Walsh ES, Hamilton K, Buser CA, Hardwick J, Tao W, Beck SC, Mao X, Lobell RB, Sepp-Lorenzino L, Yan Y, Ikuta M, Munshi SK, Kuo LC, Kreatsoulas C, Bioorg Med Chem Lett. 2006 Dec 1;16(23):6049-53. Epub 2006 Sep 15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16978863 16978863]
 [[Category: Homo sapiens]]
 [[Category: Non-specific serine/threonine protein kinase]]
@@ Line 21: / Line 30: @@
 [[Category: kinase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:44:01 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 17:19:29 2008''