Abstract
Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations of cyclic 3',5'-adenosine and guanosine monophosphates (cAMP and cGMP, respectively) by hydrolyzing them to AMP and GMP, respectively. Family-selective inhibitors of PDEs have been studied for treatment of various human diseases. However, the catalytic mechanism of cyclic nucleotide hydrolysis by PDEs has remained unclear. We determined the crystal structure of the human PDE4D2 catalytic domain in complex with AMP at 2.4 A resolution. In this structure, two divalent metal ions simultaneously interact with the phosphate group of AMP, implying a binuclear catalysis. In addition, the structure suggested that a hydroxide ion or a water bridging two metal ions may serve as the nucleophile for the hydrolysis of the cAMP phosphodiester bond.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
3',5'-Cyclic-AMP Phosphodiesterases / chemistry*
-
3',5'-Cyclic-AMP Phosphodiesterases / metabolism
-
Adenosine Monophosphate / chemistry*
-
Adenosine Monophosphate / metabolism
-
Amino Acid Sequence
-
Binding Sites
-
Catalysis
-
Catalytic Domain*
-
Cations, Divalent / chemistry
-
Crystallization
-
Crystallography, X-Ray
-
Cyclic Nucleotide Phosphodiesterases, Type 4
-
Humans
-
Hydrolysis
-
Metals / chemistry
-
Models, Molecular
-
Molecular Sequence Data
-
Protein Conformation
-
Protein Structure, Secondary
-
Protein Subunits / chemistry
-
Protein Subunits / metabolism
-
Recombinant Proteins / chemistry
-
Recombinant Proteins / isolation & purification
Substances
-
Cations, Divalent
-
Metals
-
Protein Subunits
-
Recombinant Proteins
-
Adenosine Monophosphate
-
3',5'-Cyclic-AMP Phosphodiesterases
-
Cyclic Nucleotide Phosphodiesterases, Type 4