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J. Biol. Chem., Vol. 281, Issue 43, 32861-32869, October 27, 2006

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Structural Basis for the Mechanistic Understanding of Human CD38-controlled Multiple Catalysis^*

Qun Liu¹, Irina A. Kriksunov¹, Richard Graeff, Cyrus Munshi, Hon Cheung Lee^¶2, and Quan Hao³

From the Macromolecular Diffraction Facility at the Cornell High Energy Synchrotron Source (MacCHESS), Cornell University, Ithaca, New York 14853, the Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, and the^¶Department of Physiology, University of Hong Kong, Hong Kong, China

The enzymatic cleavage of the nicotinamide-glycosidic bond on nicotinamide adenine dinucleotide (NAD⁺) has been proposed to go through an oxocarbenium ion-like transition state. Because of the instability of the ionic intermediate, there has been no structural report on such a transient reactive species. Human CD38 is an ectoenzyme that can use NAD⁺ to synthesize two calcium-mobilizing molecules. By using NAD⁺ and a surrogate substrate, NGD⁺, we captured and determined crystal structures of the enzyme complexed with an intermediate, a substrate, and a product along the reaction pathway. Our results showed that the intermediate is stabilized by polar interactions with the catalytic residue Glu²²⁶ rather than by a covalent linkage. The polar interactions between Glu²²⁶ and the substrate 2',3'-OH groups are essential for initiating catalysis. Ser¹⁹³ was demonstrated to have a regulative role during catalysis and is likely to be involved in intermediate stabilization. In addition, a product inhibition effect by ADP-ribose (through the reorientation of the product) or GDP-ribose (through the formation of a covalently linked GDP-ribose dimer) was observed. These structural data provide insights into the understanding of multiple catalysis and clues for drug design.

Received for publication, July 5, 2006 , and in revised form, August 29, 2006.

The atomic coordinates and structure factors (code 2I65, 2I67, and 2I66) 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 Grants RR01646 (to MacCHESS) and GM061568 (to H. C. L. and Q. H.) from the National Institutes of Health. 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 These authors contributed equally to this work.

² To whom correspondence may be addressed: Dept. of Physiology, University of Hong Kong, Hong Kong, China. Tel.: 852-2819-9163; Fax: 852-2819-9230; E-mail: leehc{at}tc.umn.edu.

³ To whom correspondence may be addressed: MacCHESS, Cornell High Energy Synchrotron Source, Cornell University, Ithaca, NY 14853. Tel.: 607-255-8983; Fax: 607-255-9001; E-mail: qh22{at}cornell.edu.

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