1zkl: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
[[Image:1zkl.gif|left|200px]] | [[Image:1zkl.gif|left|200px]] | ||
'''Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases''' | {{Structure | ||
|PDB= 1zkl |SIZE=350|CAPTION= <scene name='initialview01'>1zkl</scene>, resolution 1.67Å | |||
|SITE= | |||
|LIGAND= <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene> and <scene name='pdbligand=IBM:3-ISOBUTYL-1-METHYLXANTHINE'>IBM</scene> | |||
|ACTIVITY= [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] | |||
|GENE= PDE7A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |||
}} | |||
'''Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases''' | |||
==Overview== | ==Overview== | ||
| Line 7: | Line 16: | ||
==About this Structure== | ==About this Structure== | ||
1ZKL is a [ | 1ZKL 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=1ZKL OCA]. | ||
==Reference== | ==Reference== | ||
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:[http:// | 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:[http://www.ncbi.nlm.nih.gov/pubmed/15994308 15994308] | ||
[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]] | [[Category: 3',5'-cyclic-nucleotide phosphodiesterase]] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
| Line 24: | Line 33: | ||
[[Category: pde]] | [[Category: pde]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 15:36:40 2008'' | ||
Revision as of 16:36, 20 March 2008
| |||||||
| , resolution 1.67Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , and | ||||||
| Gene: | PDE7A (Homo sapiens) | ||||||
| Activity: | 3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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 Thu Mar 20 15:36:40 2008