1zkl

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{{STRUCTURE_1zkl| PDB=1zkl | SCENE= }}
{{STRUCTURE_1zkl| PDB=1zkl | SCENE= }}
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'''Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases'''
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===Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_15994308}}
==About this Structure==
==About this Structure==
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[[Category: Wang, H.]]
[[Category: Wang, H.]]
[[Category: Pde]]
[[Category: Pde]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 17:44:29 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 05:03:40 2008''

Revision as of 02:03, 28 July 2008

Image:1zkl.png

Template:STRUCTURE 1zkl

Multiple Determinants for Inhibitor Selectivity of Cyclic Nucleotide Phosphodiesterases

Template:ABSTRACT PUBMED 15994308

About this Structure

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

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:15994308

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