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The X-ray crystal structure of human beta-hexosaminidase B provides new insights into Sandhoff disease

Maier, T. and Strater, N. and Schuette, C. G. and Klingenstein, R. and Sandhoff, K. and Saenger, W.. (2003) The X-ray crystal structure of human beta-hexosaminidase B provides new insights into Sandhoff disease. Journal of Molecular Biology, 328 (3). pp. 669-681.

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Official URL: http://edoc.unibas.ch/45826/

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Abstract

Human lysosomal beta-hexosaminidases are dimeric enzymes composed of alpha and beta-chains, encoded by the genes HEXA and HEXB. They occur in three isoforms, the homodimeric hexosaminidases B (betabeta) and S (alphaalpha), and the heterodimeric hexosaminidase A (alphabeta), where dimerization is required for catalytic activity. Allelic variations in the HEXA and HEXB genes cause the fatal inborn errors of metabolism Tay-Sachs disease and Sandhoff disease, respectively. Here, we present the crystal structure of a complex of human beta-hexosaminidase B with a transition state analogue inhibitor at 2.3 Angstrom resolution (pdb 1o7a). On the basis of this structure and previous studies on related enzymes, a retaining double-displacement mechanism for glycosyl hydrolysis by beta-hexosaminidase B is proposed. In the dimer structure, which is derived from an analysis of crystal packing, most of the mutations causing late-onset,Sandhoff disease reside near the dimer interface and are proposed to interfere with correct dimer formation. The structure reported here is a valid template also for the dimeric structures of beta-hexosaminidase A and S. (C) 2003 Elsevier Science Ltd. All rights reserved.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
UniBasel Contributors:Maier, Timm
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0022-2836
e-ISSN:1089-8638
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:23 Nov 2017 08:07
Deposited On:23 Nov 2017 08:07

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