1zkl: Difference between revisions

Revision as of 17:44, 3 May 2008

Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases

OverviewOverview

Phosphodiesterase (PDE) inhibitors have been widely studied as therapeutics for treatment of human diseases. However, the mechanism by which each PDE family recognizes selectively a category of inhibitors remains a puzzle. Here we report the crystal structure of PDE7A1 catalytic domain in complex with non-selective inhibitor 3-isobutyl-1-methylxanthine and kinetic analysis on the mutants of PDE7A1 and PDE4D2. Our studies suggest at least three elements play critical roles in inhibitor selectivity: 1) the conformation and position of an invariant glutamine, 2) the natures of scaffolding residues, and 3) residues that alter shape and size of the binding pocket. Kinetic analysis shows that single PDE7 to PDE4 mutations increase the sensitivity of PDE7 to PDE4 inhibitors but are not sufficient to render the engineered enzymes comparable with the wild types. The triple S373Y/S377T/I412S mutation of PDE7A1 produces a PDE4-like enzyme, implying that multiple elements must work together to determine inhibitor selectivity.

About this StructureAbout this Structure

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

ReferenceReference

Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7., Wang H, Liu Y, Chen Y, Robinson H, Ke H, J Biol Chem. 2005 Sep 2;280(35):30949-55. Epub 2005 Jul 1. PMID:15994308 Page seeded by OCA on Sat May 3 17:44:29 2008

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OCA

@@ Line 1: / Line 1: @@
 [[Image:1zkl.gif|left|200px]]
- {{Structure
+<!--
-|PDB= 1zkl |SIZE=350|CAPTION= <scene name='initialview01'>1zkl</scene>, resolution 1.67&Aring;
+The line below this paragraph, containing "STRUCTURE_1zkl", 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=IBM:3-ISOBUTYL-1-METHYLXANTHINE'>IBM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= PDE7A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
+-->
-|DOMAIN=
+{{STRUCTURE_1zkl|  PDB=1zkl  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1zkl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1zkl OCA], [http://www.ebi.ac.uk/pdbsum/1zkl PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1zkl RCSB]</span>
-}}
 '''Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases'''
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 [[Category: Robinson, H.]]
 [[Category: Wang, H.]]
-[[Category: pde]]
+[[Category: Pde]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 17:44:29 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 01:38:01 2008''