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J. Biol. Chem., Vol. 283, Issue 28, 19657-19664, July 11, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/28/19657    most recent M800595200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Handa, N. Articles by Yokoyama, S. PubMed PubMed Citation Articles by Handa, N. Articles by Yokoyama, S. Social Bookmarking                      What's this?

Crystal Structure of the GAF-B Domain from Human Phosphodiesterase 10A Complexed with Its Ligand, cAMP^*

Noriko Handa, Eiichi Mizohata¹, Seiichiro Kishishita, Mitsutoshi Toyama, Satoshi Morita, Tomomi Uchikubo-Kamo, Ryogo Akasaka, Kenji Omori, Jun Kotera, Takaho Terada, Mikako Shirouzu, and Shigeyuki Yokoyama^¶2

From the Systems and Structural Biology Center, Yokohama Institute, RIKEN, Yokohama 230-0045, the Advanced Medical Research Laboratory, Mitsubishi Tanabe Pharma Corporation, Saitama 335-8505, and the ^¶Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan

Cyclic nucleotide phosphodiesterases (PDEs) catalyze the degradation of the cyclic nucleotides cAMP and cGMP, which are important second messengers. Five of the 11 mammalian PDE families have tandem GAF domains at their N termini. PDE10A may be the only mammalian PDE for which cAMP is the GAF domain ligand, and it may be allosterically stimulated by cAMP. PDE10A is highly expressed in striatal medium spiny neurons. Here we report the crystal structure of the C-terminal GAF domain (GAF-B) of human PDE10A complexed with cAMP at 2.1-Å resolution. The conformation of the PDE10A GAF-B domain monomer closely resembles those of the GAF domains of PDE2A and the cyanobacterium Anabaena cyaB2 adenylyl cyclase, except for the helical bundle consisting of 1, 2, and 5. The PDE10A GAF-B domain forms a dimer in the crystal and in solution. The dimerization is mainly mediated by hydrophobic interactions between the helical bundles in a parallel arrangement, with a large buried surface area. In the PDE10A GAF-B domain, cAMP tightly binds to a cNMP-binding pocket. The residues in the 3 and 4 helices, the β6 strand, the loop between 3₁₀ and 4, and the loop between 4 and β5 are involved in the recognition of the phosphate and ribose moieties. This recognition mode is similar to those of the GAF domains of PDE2A and cyaB2. In contrast, the adenine base is specifically recognized by the PDE10A GAF-B domain in a unique manner, through residues in the β1 and β2 strands.

Received for publication, January 23, 2008 , and in revised form, April 25, 2008.

The atomic coordinates and structure factors (code 2ZMF) 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 the RIKEN Structural Genomics/Proteomics Initiative (RSGI), the National Project on Protein Structural and Functional Analyses, Ministry of Education, Culture, Sports, Science and Technology of Japan. 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.

¹ Present address: MPC Group, Division of Molecular Biosciences, Imperial College London, Exhibition Road, London SW7 2AZ, UK and the Membrane Protein Lab (MPL), Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0DE, United Kingdom.

² To whom correspondence should be addressed: Systems and Structural Biology Center, Yokohama Institute, RIKEN, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan. Fax: 81-45-503-9195; E-mail: yokoyama{at}biochem.s.u-tokyo.ac.jp.

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