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Title: The Molecular Basis for Different Recognition of Substrates by Phosphodiesterase Families 4 and 10

Abstract

Phosphodiesterases (PDEs) are key enzymes that control the cellular concentrations of the second messengers cAMP and cGMP. The mechanism for selective recognition of substrates cAMP and cGMP by individual PDE families remains a puzzle. To understand the mechanism for substrate recognition by PDE enzymes, the crystal structure of the catalytic domain of an inactive D201N mutant of PDE4D2 in complex with substrate cAMP has been determined at 1.56 Angstroms resolution. The structure shows that Gln369 forms only one hydrogen bond with the adenine of cAMP. This finding provides experimental evidence against the hypothesis of two hydrogen bonds between the invariant glutamine and the substrate cAMP in PDE4, and thus suggests that the widely circulated 'glutamine switch' model is unlikely the mechanism for substrate recognition by PDEs. A structure comparison between PDE4D2-cAMP and PDE10A2-cAMP reveals an anti configuration of cAMP in PDE4D2 but syn in PDE10A2, in addition to different contact patterns of cAMP in these two structures. These observations imply that individual PDE families have their characteristic mechanisms for substrate recognition.

Authors:
; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959739
Report Number(s):
BNL-82725-2009-JA
Journal ID: ISSN 0022-2836; JMOBAK; TRN: US201016%%883
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Molecular Biology; Journal Volume: 371
Country of Publication:
United States
Language:
English
Subject:
08 HYDROGEN; 36 MATERIALS SCIENCE; ADENINES; CONFIGURATION; CRYSTAL STRUCTURE; ENZYMES; GLUTAMINE; HYDROGEN; HYPOTHESIS; MUTANTS; PHOSPHODIESTERASES; RESOLUTION; SUBSTRATES; national synchrotron light source

Citation Formats

Wang,H., Robinson, H., and Ke, H. The Molecular Basis for Different Recognition of Substrates by Phosphodiesterase Families 4 and 10. United States: N. p., 2007. Web. doi:10.1016/j.jmb.2007.05.060.
Wang,H., Robinson, H., & Ke, H. The Molecular Basis for Different Recognition of Substrates by Phosphodiesterase Families 4 and 10. United States. doi:10.1016/j.jmb.2007.05.060.
Wang,H., Robinson, H., and Ke, H. Mon . "The Molecular Basis for Different Recognition of Substrates by Phosphodiesterase Families 4 and 10". United States. doi:10.1016/j.jmb.2007.05.060.
@article{osti_959739,
title = {The Molecular Basis for Different Recognition of Substrates by Phosphodiesterase Families 4 and 10},
author = {Wang,H. and Robinson, H. and Ke, H.},
abstractNote = {Phosphodiesterases (PDEs) are key enzymes that control the cellular concentrations of the second messengers cAMP and cGMP. The mechanism for selective recognition of substrates cAMP and cGMP by individual PDE families remains a puzzle. To understand the mechanism for substrate recognition by PDE enzymes, the crystal structure of the catalytic domain of an inactive D201N mutant of PDE4D2 in complex with substrate cAMP has been determined at 1.56 Angstroms resolution. The structure shows that Gln369 forms only one hydrogen bond with the adenine of cAMP. This finding provides experimental evidence against the hypothesis of two hydrogen bonds between the invariant glutamine and the substrate cAMP in PDE4, and thus suggests that the widely circulated 'glutamine switch' model is unlikely the mechanism for substrate recognition by PDEs. A structure comparison between PDE4D2-cAMP and PDE10A2-cAMP reveals an anti configuration of cAMP in PDE4D2 but syn in PDE10A2, in addition to different contact patterns of cAMP in these two structures. These observations imply that individual PDE families have their characteristic mechanisms for substrate recognition.},
doi = {10.1016/j.jmb.2007.05.060},
journal = {Journal of Molecular Biology},
number = ,
volume = 371,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}
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