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J. Biol. Chem., Vol. 282, Issue 39, 29052-29058, September 28, 2007

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Crystal Structures of Complexes of N-Butyl- and N-Nonyl-Deoxynojirimycin Bound to Acid -Glucosidase

INSIGHTS INTO THE MECHANISM OF CHEMICAL CHAPERONE ACTION IN GAUCHER DISEASE^*

Boris Brumshtein, Harry M. Greenblatt, Terry D. Butters, Yoseph Shaaltiel^¶, David Aviezer^¶, Israel Silman^||, Anthony H. Futerman^**1, and Joel L. Sussman²

From the Departments of Structural Biology, ^||Neurobiology, and ^**Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel, Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom, and ^¶Protalix Biotherapeutics, 2 Snunit Street, Science Park, Carmiel 20100, Israel

Gaucher disease is caused by mutations in the gene encoding acid -glucosidase (GlcCerase), resulting in glucosylceramide (GlcCer) accumulation. The only currently available orally administered treatment for Gaucher disease is N-butyl-deoxynojirimycin (Zavesca^TM, NB-DNJ), which partially inhibits GlcCer synthesis, thus reducing levels of GlcCer accumulation. NB-DNJ also acts as a chemical chaperone for GlcCerase, although at a different concentration than that required to completely inhibit GlcCer synthesis. We now report the crystal structures, at 2Å resolution, of complexes of NB-DNJ and N-nonyl-deoxynojirimycin (NN-DNJ) with recombinant human GlcCerase, expressed in cultured plant cells. Both inhibitors bind at the active site of GlcCerase, with the imino sugar moiety making hydrogen bonds to side chains of active site residues. The alkyl chains of NB-DNJ and NN-DNJ are oriented toward the entrance of the active site where they undergo hydrophobic interactions. Based on these structures, we make a number of predictions concerning (i) involvement of loops adjacent to the active site in the catalytic process, (ii) the nature of nucleophilic attack by Glu-340, and (iii) the role of a conserved water molecule located in a solvent cavity adjacent to the active site. Together, these results have significance for understanding the mechanism of action of GlcCerase and the mode of GlcCerase chaperoning by imino sugars.

Received for publication, June 18, 2007 , and in revised form, July 30, 2007.

The atomic coordinates and structure factors (code 2v3d, 2v3e) 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 in part by the Magneton Program, Office of the Chief Scientist, Ministry of Industry and Commerce, Israel, the Nalvyco Foundation, the Bruce Rosen Foundation, the William Singer Foundation, the Jean and Jula Goldwurm Memorial Foundation, the Kimmelman Center for Biomolecular Structure and Assembly, the Benziyo Center for Neuroscience, an Israel Ministry of Science, Culture, and Sport grant for the Israel Structural Proteomics Center, the Divadol Foundation, the Neuman Foundation, the Israel Science Foundation, and the European Commission Sixth Framework Research and Technological Development Programme "SPINE2-COMPLEXES" Project under contract 03122. 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.

² Morton and Gladys Pickman Professor of Structural Biology at the Weizmann Institute.

¹ Jospeh Meyerhoff Professor of Biochemstry at the Weizmann Institute of Science. To whom correspondence should be addressed. Tel.: 972-8-9342704; Fax: 972-8-9344112; E-mail: tony.futerman{at}weizmann.ac.il.

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