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J. Biol. Chem., Vol. 278, Issue 46, 46021-46028, November 14, 2003

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Structural Evidence That Brain Cyclic Nucleotide Phosphodiesterase Is a Member of the 2H Phosphodiesterase Superfamily^*

Guennadi Kozlov, John Lee, Demetra Elias, Michel Gravel, Pablo Gutierrez, Irena Ekiel, Peter E. Braun, and Kalle Gehring¶

From the Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada and the Health Sector, Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec H4P 2R2, Canada

2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNP) is an enzyme abundantly present in the central nervous system of mammals and some vertebrates. In vitro, CNP specifically catalyzes the hydrolysis of 2',3'-cyclic nucleotides to produce 2'-nucleotides, but the physiologically relevant in vivo substrate remains obscure. Here, we report the medium resolution NMR structure of the catalytic domain of rat CNP with phosphate bound and describe its binding to CNP inhibitors. The structure has a bilobal arrangement of two modules, each consisting of a four-stranded -sheet and two -helices. The -sheets form a large cavity containing a number of positively charged and aromatic residues. The structure is similar to those of the cyclic phosphodiesterase from Arabidopsis thaliana and the 2'-5' RNA ligase from Thermus thermophilus, placing CNP in the superfamily of 2H phosphodiesterases that contain two tetrapeptide HX(T/S)X motifs. NMR titrations of the CNP catalytic domain with inhibitors and kinetic studies of site-directed mutants reveal a protein conformational change that occurs upon binding.

Received for publication, May 16, 2003 , and in revised form, July 28, 2003.

The atomic coordinates and structure factors (code 1N4T) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by a Canadian Institutes of Health Research grant (to K. G. and P. E. B.) and the Canadian Foundation for Innovation. Preliminary studies were supported by the Ontario Research and Development Challenge Fund and Multiple Sclerosis Society of Canada. NANUC is funded by the Canadian Institutes of Health Research, the Natural Science and Engineering Research Council of Canada, and the University of Alberta. This is National Research Council of Canada Publication 46157. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada. Tel.: 514-398-7287; Fax: 514-398-7384; E-mail: kalle.gehring{at}bri.nrc.ca.

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