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Science 288 (5472): 1822-1825

Copyright © 2000 by the American Association for the Advancement of Science

Atomic Structure of PDE4: Insights into Phosphodiesterase Mechanism and Specificity

Robert X. Xu, 1 Anne M. Hassell, 1 Dana Vanderwall, 1 Millard H. Lambert, 1 William D. Holmes, 2 Michael A. Luther, 2 Warren J. Rocque, 2 Michael V. Milburn, 1 Yingdong Zhao, 3* Hengming Ke, 3dagger Robert T. Nolte 1dagger

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.

1 Department of Structural Chemistry,
2 Department of Molecular Sciences, Glaxo Wellcome Research and Development, Research Triangle Park, NC 27709, USA.
3 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
*   Present address: Molecular Statistics and Bioinformatics Section, National Cancer Institute, Bethesda, MD 20892, USA.

dagger    To whom correspondence should be addressed.

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