1z1l
From Proteopedia
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'''The Crystal Structure of the Phosphodiesterase 2A Catalytic Domain''' | '''The Crystal Structure of the Phosphodiesterase 2A Catalytic Domain''' | ||
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[[Category: Kohls, D.]] | [[Category: Kohls, D.]] | ||
[[Category: Low, C.]] | [[Category: Low, C.]] | ||
| - | [[Category: | + | [[Category: Crystal structure]] |
| - | [[Category: | + | [[Category: Pde 2a]] |
| - | [[Category: | + | [[Category: Phosphodiesterase]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 17:04:39 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 14:04, 3 May 2008
The Crystal Structure of the Phosphodiesterase 2A Catalytic Domain
Overview
Phosphodiesterases (PDEs) modulate signaling by cyclic nucleotides in diverse processes such as cardiac contractility, platelet aggregation, lipolysis, glycogenolysis, and smooth muscle contraction. Cyclic guanosine monophosphate (cGMP) stimulated human phosphodiesterase 2 (PDE2) is expressed mainly in brain and heart tissues. PDE2A is involved in the regulation of blood pressure and fluid homeostasis by the atrial natriuretic peptide (ANP), making PDE2-type enzymes important targets for drug discovery. The design of more potent and selective inhibitors of PDE2A for the treatment of heart disease would be greatly aided by the identification of active site residues in PDE2A that determine substrate and inhibitor selectivity. The identification of active site residues through traditional mutational studies involves the time-consuming and tedious purification of a large number of mutant proteins from overexpressing cells. Here we report an alternative approach to rapidly produce active site mutants of human PDE2A and identify their enzymatic properties using a wheat germ in vitro translation (IVT, also known as cell-free translation) system. We also present the crystal structure of the catalytic domain of human PDE2A determined at 1.7 A resolution, which provided a framework for the rational design of active site mutants. Using a rapid IVT approach for expression of human PDE2A mutants, we identified the roles of active site residues Asp811, Gln812, Ile826, and Tyr827 in inhibitor and substrate selectivity for PDE2A.
About this Structure
1Z1L is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system., Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T, Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 Page seeded by OCA on Sat May 3 17:04:39 2008
