Substrate specificity and inhibitor selectivity of pde

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Project Title: Substrate specificity and inhibitor selectivity of pde
Principal Investigators (PI): KE HENGMING
Project Number: 3R01GM059791-08S1
Organization: UNIVERSITY OF NORTH CAROLINA CHAPEL HILL
 
Project Description:
Cyclic nucleotide phosphodiesterases (PDEs) are the key enzymes that control the cellular concentration of "second messengers" adenosine or guanosine 3', 5'-cyclic monophosphate (cAMP or cGMP). The human genome encodes 21 PDE genes and over 60 PDE isoforms categorized into 11 families. All PDEs contain a conserved catalytic domain, but each family possesses individual substrate specificity and selective inhibitors. Selective inhibitors of PDEs have been widely studied as therapeutic agents for various diseases. For example, PDEs inhibitor sildenafil (VIAGRA(tm)) is a drug for erectile dysfunction and PDE3 inhibitor cilostazole (Pletal(tm)) is a drug for intermittent claudication. The wide medical applications of PDE inhibitors have attracted great attention from both academic and industrial research groups. However, it has been mysteries how the similar active sites of PDEs distinguish the different substrates and inhibitors. We hypothesize that the substrate specificity and inhibitor selectivity are determined by both the chemical nature of active site residues and the conformations of the PDE active sites. This proposal chooses cAMP specific PDE4 and cGMP specific PDE5 and PDE9 as the target systems to study the substrate specificity and inhibitor selectivity with approaches of crystallography and protein engineering. The structures of PDE4, PDES and PDE9 in complex with substrate, substrate analogues, and selective inhibitors will be determined. The candidate residues will be switched between PDE4 and PDE5 by a single or multiple mutations for further illustration of the substrate specificity. The structures in this proposal, together with those from the last funding period, will reveal key residues and elements for determination of the substrate specificity and identify potential subpockets contributing to the selective binding of the inhibitors. Since the inhibitor selectivity is a key issue for side effects of drugs, the structures of PDEs in complex with inhibitors will provide templates for design of family- or subfamily-selective inhibitors and ultimately improve the drugs efficiency for treatment of the diseases.
 
Project Terms:
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Project Title: Substrate specificity and inhibitor selectivity of pde
Principal Investigators (PI): KE HENGMING
Project Number: 3R01GM059791-08S1
Organization: UNIVERSITY OF NORTH CAROLINA CHAPEL HILL
 
Other Information:
Fiscal Year: 2009
Project Start Date: 25 September 2009
Project End Date: 31 July 2011
Administering Institute Or Center: GM
 
Project Funding Information:
Total Funding: $217,542
Year Funding Organization Total Funding, $
2009 NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES $217,542
Project Title: Substrate specificity and inhibitor selectivity of pde
Principal Investigators (PI): KE HENGMING
Project Number: 3R01GM059791-08S1
Organization: UNIVERSITY OF NORTH CAROLINA CHAPEL HILL
 
Project_number Title Year FY Total Cost
There are no results for this project in database.
Project Title: Substrate specificity and inhibitor selectivity of pde
Principal Investigators (PI): KE HENGMING
Project Number: 3R01GM059791-08S1
Organization: UNIVERSITY OF NORTH CAROLINA CHAPEL HILL
 
Project number Project title Organization FY Funding Organization FY Total Cost
5R01GM059791-04CRYSTAL STRUCT. OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASEUNIVERSITY OF NORTH CAROLINA CHAPEL HILL2003NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
$181,875
5R01GM059791-03CRYSTAL STRUCT. OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASEUNIVERSITY OF NORTH CAROLINA CHAPEL HILL2002NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
$181,875
5R01GM059791-02CRYSTAL STRUCT. OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASEUNIVERSITY OF NORTH CAROLINA CHAPEL HILL2001NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
$181,719
1R01GM059791-01A1CRYSTAL STRUCT. OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASEUNIVERSITY OF NORTH CAROLINA CHAPEL HILL2000NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
$187,979
2R01GM059791-05A2Substrate specificity and inhibitor selectivity of PDEUNIVERSITY OF NORTH CAROLINA CHAPEL HILL2005NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
$247,485
5R01GM059791-06Substrate specificity and inhibitor selectivity of PDEUNIVERSITY OF NORTH CAROLINA CHAPEL HILL2006NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
$241,669
5R01GM059791-07Substrate specificity and inhibitor selectivity of PDEUNIVERSITY OF NORTH CAROLINA CHAPEL HILL2007NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
$234,661
5R01GM059791-08Substrate specificity and inhibitor selectivity of PDEUNIVERSITY OF NORTH CAROLINA CHAPEL HILL2008NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
$234,661
3R01GM059791-08S1Substrate specificity and inhibitor selectivity of PDEUNIVERSITY OF NORTH CAROLINA CHAPEL HILL2009NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
$217,542
Project Title: Substrate specificity and inhibitor selectivity of pde
Principal Investigators (PI): KE HENGMING
Project Number: 3R01GM059791-08S1
Organization: UNIVERSITY OF NORTH CAROLINA CHAPEL HILL
 
Project number Project title Principal investigator
There are no any related projects.
Project Title: Substrate specificity and inhibitor selectivity of pde
Principal Investigators (PI): KE HENGMING
Project Number: 3R01GM059791-08S1
Organization: UNIVERSITY OF NORTH CAROLINA CHAPEL HILL
 
Title Abstract Authors Year Rel
Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte. Development (Cambridge, England). 2009 Jun 136 (11) :1869-78 Norris, Rachael P; Ratzan, William J; Freudzon, Marina; Mehlmann, Lisa M; Krall, Judith; Movsesian, Matthew A; Wang, Huanchen; Ke, Hengming; Nikolaev, Viacheslav O; Jaffe, Laurinda A 2009
Refolding and kinetic characterization of the phosphodiesterase-8A catalytic domain. Protein expression and purification. 2009 Mar 64 (1) :82-8 Yan, Zier; Wang, Huanchen; Cai, Jiwen; Ke, Hengming 2009