Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity.
Cyclic nucleotides are second messengers that are essential in vision, muscle contraction, neurotransmission, exocytosis, cell growth, and differentiation. These molecules are degraded by a family of enzymes known as phosphodiesterases, which serve a critical function by regulating the intracellular concentration of cyclic nucleotides. We have determined the three-dimensional structure of the catalytic domain of phosphodiesterase 4B2B to 1.77 angstrom resolution. The active site has been identified and contains a cluster of two metal atoms. The structure suggests the mechanism of action and basis for specificity and will provide a framework for structure-assisted drug design for members of the phosphodiesterase family.
Xu
R X
RX
Department of Structural Chemistry, Department of Molecular Sciences, Glaxo Wellcome Research and Development, Research Triangle Park, NC 27709, USA.
Hassell
A M
AM
Vanderwall
D
D
Lambert
M H
MH
Holmes
W D
WD
Luther
M A
MA
Rocque
W J
WJ
Milburn
M V
MV
Zhao
Y
Y
Ke
H
H
Nolte
R T
RT
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D020134:Catalytic Domain; D003460:Crystallization; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000737:chemistry / Q000378:metabolism*; D006152:Cyclic GMP / Q000737:chemistry / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006860:Hydrogen Bonding; D006868:Hydrolysis; D008670:Metals / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013379:Substrate Specificity
D008670:Metals; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006152:Cyclic GMP