1np0
From Proteopedia
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| , resolution 2.50Å | |||||||
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| Ligands: | , and | ||||||
| Activity: | Beta-N-acetylhexosaminidase, with EC number 3.2.1.52 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Human lysosomal beta-hexosaminidase isoform B in complex with intermediate analogue NAG-thiazoline
Contents |
Overview
In humans, two major beta-hexosaminidase isoenzymes exist: Hex A and Hex B. Hex A is a heterodimer of subunits alpha and beta (60% identity), whereas Hex B is a homodimer of beta-subunits. Interest in human beta-hexosaminidase stems from its association with Tay-Sachs and Sandhoff disease; these are prototypical lysosomal storage disorders resulting from the abnormal accumulation of G(M2)-ganglioside (G(M2)). Hex A degrades G(M2) by removing a terminal N-acetyl-D-galactosamine (beta-GalNAc) residue, and this activity requires the G(M2)-activator, a protein which solubilizes the ganglioside for presentation to Hex A. We present here the crystal structure of human Hex B, alone (2.4A) and in complex with the mechanistic inhibitors GalNAc-isofagomine (2.2A) or NAG-thiazoline (2.5A). From these, and the known X-ray structure of the G(M2)-activator, we have modeled Hex A in complex with the activator and ganglioside. Together, our crystallographic and modeling data demonstrate how alpha and beta-subunits dimerize to form either Hex A or Hex B, how these isoenzymes hydrolyze diverse substrates, and how many documented point mutations cause Sandhoff disease (beta-subunit mutations) and Tay-Sachs disease (alpha-subunit mutations).
Disease
Known diseases associated with this structure: Sandhoff disease, infantile, juvenile, and adult forms OMIM:[606873], Spinal muscular atrophy, juvenile OMIM:[606873]
About this Structure
1NP0 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Crystal structure of human beta-hexosaminidase B: understanding the molecular basis of Sandhoff and Tay-Sachs disease., Mark BL, Mahuran DJ, Cherney MM, Zhao D, Knapp S, James MN, J Mol Biol. 2003 Apr 11;327(5):1093-109. PMID:12662933
Page seeded by OCA on Thu Mar 20 12:59:45 2008
