Download MendeleyThe X-Ray Crystal Structure of Human Beta-Hexosaminidase B Provides New Insights Into Sandhoff Disease
Maier, T., Strater, N., Schuette, C., Klingenstein, R., Sandhoff, K., Saenger, W.(2003) J Mol Biol 328: 669
- PubMed: 12706724
- DOI: https://doi.org/10.1016/s0022-2836(03)00311-5
- Primary Citation of Related Structures:
1O7A - PubMed 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 2.3A 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.
Organizational Affiliation:
Institut f¨¹r Chemie Kristallographie, Freie Universit?t Berlin, Takustrasse 6, 14195 Berlin, Germany.
