1zkl: Difference between revisions

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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 with , and as ligands. Active as 3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17 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

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 '''Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases'''<br />
 ==Overview==
-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.
+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 Structure==
-ZKL 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 ZN, MG and IBM as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1ZKL OCA].
+ZKL 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=ZN:'>ZN</scene>, <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=IBM:'>IBM</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ZKL OCA].
 ==Reference==
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 [[Category: pde]]
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