1np0

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spinqualitylabelsall models 1np0, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Human lysosomal beta-hexosaminidase isoform B in complex with intermediate analogue NAG-thiazoline

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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 with SO4, NGT and GOL as ligands. Active as Beta-N-acetylhexosaminidase, with EC number 3.2.1.52 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

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