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J. Biol. Chem., Vol. 280, Issue 9, 8471-8481, March 4, 2005

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Structure and Substrate-binding Mechanism of Human Ap₄A Hydrolase^*

James D. Swarbrick, Smrithi Buyya, Dilantha Gunawardana, Kenwyn R. Gayler, Alexander G. McLennan¶, and Paul R. Gooley||

From the Department of Biochemistry and Molecular Biology, the University of Melbourne, Parkville, Victoria 3010, Australia and ^¶School of Biological Sciences, the University of Liverpool, Liverpool L69 7ZB, United Kingdom

Asymmetric diadenosine 5',5'''-P¹,P⁴-tetraphosphate (Ap₄A) hydrolases play a major role in maintaining homeostasis by cleaving the metabolite diadenosine tetraphosphate (Ap₄A) back into ATP and AMP. The NMR solution structures of the 17-kDa human asymmetric Ap₄A hydrolase have been solved in both the presence and absence of the product ATP. The adenine moiety of the nucleotide predominantly binds in a ring stacking arrangement equivalent to that observed in the x-ray structure of the homologue from Caenorhabditis elegans. The binding site is, however, markedly divergent to that observed in the plant/pathogenic bacteria class of enzymes, opening avenues for the exploration of specific therapeutics. Binding of ATP induces substantial conformational and dynamic changes that were not observed in the C. elegans structure. In contrast to the C. elegans homologue, important side chains that play a major role in substrate binding do not have to reorient to accommodate the ligand. This may have important implications in the mechanism of substrate recognition in this class of enzymes.

Received for publication, November 1, 2004

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

^* This study was supported by the National Health and Medical Research Council of Australia. 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 may be addressed. E-mail: j.swarbrick{at}unimelb.edu.au.

^|| To whom correspondence may be addressed. E-mail: prg{at}unimelb.edu.au.

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