1h0w: Difference between revisions

Revision as of 18:16, 2 May 2008

HUMAN CYCLIN DEPENDENT PROTEIN KINASE 2 IN COMPLEX WITH THE INHIBITOR 2-AMINO-6-[CYCLOHEX-3-ENYL]METHOXYPURINE

OverviewOverview

O(6)-substituted guanines are adenosine 5'-triphosphate (ATP) competitive inhibitors of CDK1/cyclin B1 and CDK2/cyclin A, the O(6) substituent occupying the kinase ribose binding site. Fifty-eight O(6)-substituted guanines were prepared to probe the ribose pocket, and the structures of four representative compounds bound to monomeric CDK2 were determined by X-ray crystallography. Optimum binding occurs with a moderately sized aliphatic O(6) substituent that packs tightly against the hydrophobic patch presented by the glycine loop, centered on Val18, an interaction promoted by the conformational restraints imposed in a cyclohexylmethyl or cyclohexenylmethyl ring. Structure-based design generated (R)-(2-amino-9H-purin-6-yloxymethyl)pyrrolidin-2-one (56), which reproduces the reported hydrogen bonds formed between ATP and Asp86 and Gln131 but failed to improve inhibitory potency. Thus, the parent compound O(6)-cyclohexylmethylguanine (NU2058, 25) is the preferred starting point for exploring other areas of the kinase active site.

About this StructureAbout this Structure

1H0W is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives., Gibson AE, Arris CE, Bentley J, Boyle FT, Curtin NJ, Davies TG, Endicott JA, Golding BT, Grant S, Griffin RJ, Jewsbury P, Johnson LN, Mesguiche V, Newell DR, Noble ME, Tucker JA, Whitfield HJ, J Med Chem. 2002 Aug 1;45(16):3381-93. PMID:12139449 Page seeded by OCA on Fri May 2 18:16:18 2008

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

OCA

@@ Line 1: / Line 1: @@
 [[Image:1h0w.gif|left|200px]]
- {{Structure
+<!--
-|PDB= 1h0w |SIZE=350|CAPTION= <scene name='initialview01'>1h0w</scene>, resolution 2.10&Aring;
+The line below this paragraph, containing "STRUCTURE_1h0w", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=207:207+Binding+Site+For+Chain+A'>207</scene>
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=207:1-AMINO-6-CYCLOHEX-3-ENYLMETHYLOXYPURINE'>207</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[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] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_1h0w|  PDB=1h0w  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1h0w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h0w OCA], [http://www.ebi.ac.uk/pdbsum/1h0w PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1h0w RCSB]</span>
-}}
 '''HUMAN CYCLIN DEPENDENT PROTEIN KINASE 2 IN COMPLEX WITH THE INHIBITOR 2-AMINO-6-[CYCLOHEX-3-ENYL]METHOXYPURINE'''
@@ Line 43: / Line 40: @@
 [[Category: Tucker, J A.]]
 [[Category: Whitfield, H J.]]
-[[Category: cell cycle]]
+[[Category: Cell cycle]]
-[[Category: cell division]]
+[[Category: Cell division]]
-[[Category: inhibition]]
+[[Category: Inhibition]]
-[[Category: mitosis]]
+[[Category: Mitosis]]
-[[Category: phosphorylation]]
+[[Category: Phosphorylation]]
-[[Category: protein kinase]]
+[[Category: Protein kinase]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May  2 18:16:18 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 20:55:24 2008''