1ouy: Difference between revisions

Revision as of 04:18, 3 May 2008

The structure of p38 alpha in complex with a dihydropyrido-pyrimidine inhibitor

OverviewOverview

The quinazolinone and pyridol-pyrimidine classes of p38 MAP kinase inhibitors have a previously unseen degree of specificity for p38 over other MAP kinases. Comparison of the crystal structures of p38 bound to four different compounds shows that binding of the more specific molecules is characterized by a peptide flip between Met109 and Gly110. Gly110 is a residue specific to the alpha, beta and gamma isoforms of p38. The delta isoform and the other MAP kinases have bulkier residues in this position. These residues would likely make the peptide flip energetically unfavorable, thus explaining the selectivity of binding. To test this hypothesis, we constructed G110A and G110D mutants of p38 and measured the potency of several compounds against them. The results confirm that the selectivity of quinazolinones and pyridol-pyrimidines results from the presence of a glycine in position 110. This unique mode of binding may be exploited in the design of new p38 inhibitors.

About this StructureAbout this Structure

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

ReferenceReference

Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity., Fitzgerald CE, Patel SB, Becker JW, Cameron PM, Zaller D, Pikounis VB, O'Keefe SJ, Scapin G, Nat Struct Biol. 2003 Sep;10(9):764-9. Epub 2003 Aug 3. PMID:12897767 Page seeded by OCA on Sat May 3 04:18:36 2008

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

OCA

@@ Line 1: / Line 1: @@
 [[Image:1ouy.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 1ouy |SIZE=350|CAPTION= <scene name='initialview01'>1ouy</scene>, resolution 2.5&Aring;
+The line below this paragraph, containing "STRUCTURE_1ouy", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=094:1-(2,6-DICHLOROPHENYL)-6-[(2,4-DIFLUOROPHENYL)SULFANYL]-7-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)-3,4-DIHYDROPYRIDO[3,2-D]PYRIMIDIN-2(1H)-ONE'>094</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= MAPK14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+-->
-|DOMAIN=
+{{STRUCTURE_1ouy|  PDB=1ouy  |  SCENE=  }}
-|RELATEDENTRY=[[1m7q|1M7Q]], [[1ouk|1OUK]], [[1ove|1OVE]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1ouy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ouy OCA], [http://www.ebi.ac.uk/pdbsum/1ouy PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1ouy RCSB]</span>
-}}
 '''The structure of p38 alpha in complex with a dihydropyrido-pyrimidine inhibitor'''
@@ Line 34: / Line 31: @@
 [[Category: Scapin, G.]]
 [[Category: Zaller, D.]]
-[[Category: atp binding domain]]
+[[Category: Atp binding domain]]
-[[Category: hydrophobic pocket]]
+[[Category: Hydrophobic pocket]]
-[[Category: kinase domain]]
+[[Category: Kinase domain]]
-[[Category: map kinase]]
+[[Category: Map kinase]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 04:18:36 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:50:42 2008''