1o7a: Difference between revisions
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==Overview== | ==Overview== | ||
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. | 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. | ||
==Disease== | |||
Known diseases associated with this structure: Sandhoff disease, infantile, juvenile, and adult forms OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606873 606873]], Spinal muscular atrophy, juvenile OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606873 606873]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: sphingolipid degradation]] | [[Category: sphingolipid degradation]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 18:30:24 2007'' | ||
